Substituted thioacetamides

ABSTRACT

The present invention is directed to chemical compositions of substituted thioacetamides, processes for the preparation thereof and uses of the compositions in the treatment of diseases.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of application Ser.No. 09/855,228, filed May 15, 2001, now U.S. Pat. No. 6,492,396, whichclaims priority to U.S. Provisional application Serial No. 60/204,789,filed May 16, 2000 and U.S. provisional application Serial No.60/268,283, filed Feb. 13, 2001. The disclosure of each of theseapplications is hereby incorporated herein by reference in theirentireties.

FIELD OF THE INVENTION

The present invention is related to chemical compositions, processes forthe preparation thereof and uses of the composition. Particularly, thepresent invention relates to compositions that include substitutedthioacetamides, and their use in the treatment of diseases, includingtreatment of sleepiness, promotion of wakefulness, treatment ofParkinson's disease, cerebral ischemia, stroke, sleep apneas, eatingdisorders, stimulation of appetite and weight gain, treatment ofattention deficit hyperactivity disorder (“ADHD”), enhancing function indisorders associated with hypofunctionality of the cerebral cortex,including, but not limited to, depression, schizophrenia, fatigue, inparticular, fatigue associated with neurologic disease, such as multiplesclerosis, chronic fatigue syndrome, and improvement of cognitivedysfunction.

BACKGROUND OF THE INVENTION

The compounds disclosed herein are related to the biological andchemical analogs of modafinil. Modafinil, C₁₅ H₁₅NO₂S, also known as2-(benzhydrylsulfinyl) acetamide, or 2-[(diphenylmethyl) sulfinyl]acetamide, is a synthetic acetamide derivative with wake-promotingactivity, the structure of which has been described in French Patent No.78 05 510 and in U.S. Pat. No. 4,177,290 ('290), and which has beenapproved by the United States Food and Drug Administration for use inthe treatment of excessive daytime sleepiness associated withnarcolepsy. Modafinil has been tested for treatment of severalbehavioral conditions in combination with various agents includingapomorphine, amphetamine, reserpine, oxotremorine, hypnotics, yohimbine,5-hydroxytryptophan, and monoamine oxidase inhibitors, as described inthe cited patents. A method of preparation of a racemic mixture isdescribed in the '290 patent and a method of preparation of alevorotatory isomer is described in U.S. Pat. No. 4,927,855 (bothincorporated herein by reference). The levorotatory isomer is reportedto be useful for treatment of hypersomnia, depression, Alzheimer'sdisease and to have activity towards the symptoms of dementia and lossof memory, especially in the elderly.

The primary pharmacological activity of modafinil is to promotewakefulness. Modafinil promotes wakefulness in rats (Touret et al.,1995; Edgar and Seidel, 1997), cats (Lin et al., 1992), canines (Sheltonet al., 1995) and non-human primates (Hernant et al, 1991) as well as inmodels mimicking clinical situations, such as sleep apnea (Englishbulldog sleep disordered breathing model) (Panckeri et al, 1996) andnarcolepsy (narcoleptic canine) (Shelton et al, 1995).

Modafinil has also been described as an agent with activity in thecentral nervous system, and as a useful agent in the treatment ofParkinson's disease (U.S. Pat. No. 5,180,745); in the protection ofcerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in thetreatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776);and in the treatment of sleep apneas and disorders of central origin(U.S. Pat. No. 5,612,379). U.S. Pat. No. 5,618,845 describes modafinilpreparations of a defined particle size less than about 200 microns. Inaddition, modafinil may be used in the treatment of eating disorders, orto promote weight gain or stimulate appetite in humans or animals (U.S.Provisional Patent Application No. 60/150,071, incorporated herein byreference), or in the treatment of attention deficit hyperactivitydisorder (ADHD), or fatigue, especially fatigue associated with multiplesclerosis (U.S. Provisional Patent Application No. 60/149,612,incorporated herein by reference).

Several published patent applications describe derivative forms ofmodafinil and the use of modafinil derivatives in the treatment ofvarious disorders. For example, PCT publication WO 99/25329 describesanalogs of modafinil in which the phenyl groups are substituted with aF, Cl, Br, CF₃, NO₂, NH₂, C₁-C₄ alkyl, C₁-C₄ alkoxy, or methylenedioxy,and in which the amide is substituted with OH, C₁-C₄ alkyl, C₁-C₄hydroxyalkyl, or a C₁-C₄ hydrocarbon radical. These compositions aredescribed as being useful for treating drug-induced sleepiness,especially sleepiness associated with administration of morphine tocancer patients.

Similarly, U.S. Pat. No. 4,066,686 describes benzhydrylsulphinylderivatives, including modafinil derivatives with an extended alkylchain between the sulfinyl and carbonyl groups and where NR₃R₄ is NHOH.These compounds are described as being useful in therapy for treatingdisturbances of the central nervous system.

PCT publication WO 95/01333 describes modafinil derivatives that areuseful for modifying feeding behavior. The modifications to modafinildescribed include a chloro group at the 3 position of one of the phenylgroups, and a pyridyl substituted for the second phenyl, substitution ofone or two methyl groups for hydrogens at the 2-carbon position, theamide hydrogens may be substituted with one or two groups selected fromH, a pyridyl-methyl or ethyl groups, and further where the sulfur maynot be oxidized.

PCT publication WO 95/01171 also describes modified modafinil compoundsthat are said to be useful for modifying eating behavior. The describedcompounds include substitutions of 4-fluoro-, 3-fluoro-, and 4 chloro-in a first phenyl group and 4-fluoro- or 3-fluoro-substitutions in thesecond phenyl. Also described are substitutions in which the amidecontains substitutions with an OH or isopropyl group.

Terauchi, H, et al. described nicotinamide derivatives useful as ATP-aseinhibitors (Terauchi, H, et al, J. Med. Chem., 1997, 40, 313-321). Inparticular, several N-alkyl substituted 2-(Benzhydrylsulfinyl)nicotinamides are described.

U.S. Pat. Nos. 4,980,372 and 4,935,240 describebenzoylaminophenoxybutanoic acid derivatives. In particular, sulfidederivatives of modafinil containing a phenyl and substituted phenyllinker between the sulfide and carbonyl, and a substituted aryl in theterminal amide position, are disclosed.

Other modafinil derivatives have been disclosed wherein the terminalphenyl groups are constrained by a linking group. For example, in U.S.Pat. No. 5,563,169, certain xanthenyl and thiaxanthenyl derivativeshaving a substituted aryl in the terminal amide position are reported.

Other xanthenyl and thiaxanthenyl derivatives are disclosed in Annis, I;Barany, G. Pept. Proc. Am. Pept. Symp. 15^(th) (Meeting Date 1997)343-344, 1999 (preparation of a xanthenyl derivative of Ellman'sReagent, useful as a reagent in peptide synthesis); Han, Y.; Barany, G.J. Org. Chem., 1997, 62, 3841-3848 (preparation of S-xanthenyl protectedcysteine derivatives, useful as a reagent in peptide synthesis); andEl-Sakka, I. A., et al. Arch. Pharm. (Weinheim), 1994, 327, 133-135(thiaxanthenol derivatives of thioglycolic acid).

Thus, there is a need for novel classes of compounds that possessbeneficial properties. It has been discovered that a class of compounds,referred to herein as substituted thioacetamides, are useful as agentsfor treating or preventing diseases or disorders, including treatment ofsleepiness, promotion of wakefulness, treatment of Parkinson's disease,cerebral ischemia, stroke, sleep apneas, eating disorders, stimulationof appetite and weight gain, treatment of attention deficithyperactivity disorder, enhancing function in disorders associated withhypofunctionality of the cerebral cortex, including, but not limited to,depression, schizophrenia, fatigue, in particular, fatigue associatedwith neurologic disease, such as multiple sclerosis, chronic fatiguesyndrome, and improvement of cognitive dysfunction. The presentinvention is directed to these, as well as other, important ends.

SUMMARY OF THE INVENTION

One aspect of the present invention provides, in part, various novelsubstituted thioacetamides. Other aspects of the invention also includetheir pharmaceutical compositions, methods of their preparation, and useof the compounds in the treatment of diseases.

In one aspect of the invention, there are provided compounds of formula(I-A):

Constituent members and preferred embodiments are disclosed in detailinfra.

In another aspect of the invention, there are provided compounds offormula (I):

Constituent members and preferred embodiments are disclosed in detailinfra.

Another object of the present invention is to provide compounds offormula (II-A):

Constituent members and preferred embodiments are disclosed in detailinfra.

An additional object of the present invention is to provide compounds offormula (II):

Constituent members and preferred embodiments are disclosed in detailinfra.

Another object of the present invention is to provide methods oftreating or preventing diseases or disorders, including treatment ofsleepiness, promotion of wakefulness, treatment of Parkinson's disease,cerebral ischemia, stroke, sleep apneas, eating disorders, stimulationof appetite and weight gain, treatment of attention deficithyperactivity disorder, enhancing function in disorders associated withhypofunctionality of the cerebral cortex, including, but not limited to,depression, schizophrenia, fatigue, in particular, fatigue associatedwith neurologic disease, such as multiple sclerosis, chronic fatiguesyndrome, and improvement of cognitive dysfunction.

Another object of the present invention is to provide pharmaceuticalcompositions comprising the compounds of the present invention whereinthe compositions comprise one or more pharmaceutically acceptableexcipients and a therapeutically effective amount of at least one of thecompounds of the present invention, or a pharmaceutically acceptablesalt or ester form thereof.

These and other objects, features and advantages of the substitutedthioacetamides will be disclosed in the following detailed descriptionof the patent disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of data indicating EEG-determined wakefulness in ratstreated with Compound I-9 (100 mg/kg, ip; solid line) or methylcellulosevehicle (stippled line). Wakefulness is quantified in 5-minute bins.N=13 rats/group. *p<0.05 vs. vehicle treated animals.

FIG. 2 is a graph of data indicating EEG-determined wakefulness in ratstreated with compound II-23 (100 mg/kg, ip; solid triangles) ormethylcellulose vehicle (open circles). Each point represents the meanpercent of time awake for the succeeding half hour. *p<0.05 vs. vehicletreated animals.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides novel compounds offormula (I-A):

wherein:

Ar₁ and Ar₂ are each independently selected from C₆-C₁₀ aryl orheteroaryl;

wherein each of Ar₁ or Ar₂ may be independently optionally substitutedwith 1-3 substituents independently selected from:

a) H, C₆-C₁₀ aryl, heteroaryl, F, Cl, Br, I, —CN, —CF₃, —NO₂, —OH, —OR₇,—O(CH₂)_(p)NR₉R₁₀, —OC(═O)R₇, —OC(═O)NR₉R₁₀, —O(CH₂)_(p)OR₈, —CH₂OR₈,—NR₉R₁₀, —NR₈S(═O)₂R₇, —NR₈C(═O)R₇, or —NR₈C(═S)R₇;

b) —CH₂OR₁₁;

c) —NR₈C(═O)NR₉R₁₀, —NR₈C(═S)NR₉R₁₀, —CO₂R₁₂, —C(═O)R₁₃, —C(═O)NR₉R₁₀,—C(═S)NR₉R₁₀, —CH═NOR₁₂, —CH═NR₇, —(CH₂)_(p)NR₉R₁₀, —(CH₂)_(p)NHR₁₁,—CH═NNR₁₂R_(12A), —C(═NR₈)NR_(8A)R_(8B)—NR₈C(═NH)R_(8A),—NR₈C(═NH)NR_(8A)R_(8B),

d) —S(O)_(y)R₇, —(CH₂)_(p)S(O)_(y)R₇, —CH₂S(O)_(y)R₇; and

e) C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, where:

1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or

2) each alkyl, alkenyl or alkynyl group is independently substitutedwith 1 to 3 groups independently selected from C₆-C₁₀ aryl, heteroaryl,F, Cl, Br, I, CF₃, —CN, —NO₂, —OH, —OR₇, —CH₂OR₈, —NR₉R₁₀,—O—(CH₂)_(p)—OH, —S—(CH₂)_(p)—OH, —X₁(CH₂)_(p)OR₇, X₁(CH₂)_(p)NR₉R₁₀,—X₁(CH₂)_(p)C(═O)NR₉R₁₀, —X₁(CH₂)_(p)C(═S)NR₉R₁₀,—X₁(CH₂)_(p)OC(═O)NR₉R₁₀, —X₁(CH₂)_(p)CO₂R₈, —X₁(CH₂)_(p)S(O)_(y)R₇,—X₁(CH₂)_(p)NR₈C(═O)NR₉R₁₀, —C(═O)R₃, —CO₂R₁₂, —OC(═O)R₇, —C(═O)NR₉R₁₀,—OC(═O)NR₁₂R_(12A), O-tetrahydropyranyl, —C(═S)NR₉R₁₀, —CH═NNR₁₂R_(12A),—CH═NOR₁₂, —CH═NR₇, —CH═NNHCH(N═NH)NH₂, —NR₈CO₂R₇, —NR₈C(═O)NR₉R₁₀,—NR₈C(═S)NR₉R₁₀, —NHC(═NH)NH₂, —NR₈C(═O)R₇, —NR₈C(═S)R₇, —NR₈S(═O)₂R₇,—S(O)_(y)R₇, —S(═O)₂NR₁₂R_(12A), —P(═O)(OR₈)₂, —OR₁₁, and a C₅-C₇monosaccharide where each hydroxyl group of the monosaccharide isindependently either unsubstituted or is replaced by H, C₁-C₄ alkyl,C₁-C₄ alkoxy, or —O—C(═O)R₇;

X₁ is —O—, —S—, —N(R₈)—;

Y is selected from C₁-C₄ alkylene, C₆-C₁₀ arylene, heteroarylene, C₃-C₈cycloalkylene, heterocyclylene, —O—, —N(R₈)—, —S(O)_(y),—CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—, or —C≡C—; with theproviso that when Y is —O—, —N(R₈)—, or —S(O)_(y), m and n cannot be 0;R₃ and R₄ are the same or different and are each selected from H, C₁-C₆alkyl, —OH, and —CH(R₆)—CONR_(8A)R_(8B), provided that R₃ and R₄ are notboth OH; or R₃ and R₄, together with the nitrogen to which they areattached, form a 3-7 member heterocyclic ring;

R₃ and R₄ are the same or different and are each selected from H, C₁-C₆alkyl, —OH, and —CH(R₆)—CONR_(8A)R_(8B), provided that R₃ and R₄ are notboth OH; or R₃ and R₄, together with the nitrogen to which they areattached, form a 3-7 member heterocyclic ring;

R₆ is H, C₁-C₄ alkyl or the side chain of an a-amino acid;

R₇ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or heteroaryl;

R₈, R_(8A)and R_(8B)are each independently H, C₁-C₄ alkyl, or C₆-C₁₀aryl;

R₉ and R₁₀ are independently selected from H, C₁-C₄ alkyl, and C₆-C₁₀aryl; or R₉ and R₁₀ together with the nitrogen to which they areattached, form a 3-7 member heterocyclic ring;

R₁₁ is the residue of an amino acid after the hydroxyl group of thecarboxyl group is removed;

R₁₂ and R_(12A)are each independently selected from H, C₁-C₆ alkyl,cycloalkyl, C₆-C₁₀ aryl, and heteroaryl; or R₁₂ and R_(12A), togetherwith the nitrogen to which they are attached, form a 5-7 memberheterocyclic ring;

R₁₃ is H, C₁-C₆ alkyl, cycloalkyl, C₆-C₁₀ aryl, heteroaryl, —C(═O)R₇,—C(═O)NR₉R₁₀, or —C(═S)NR₉R₁₀;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is from 1, 2, 3, or 4;

q is 0, 1, or 2;

t is 2, 3, or 4;

y is 0, 1 or 2;

with the proviso that when Ar₁ is phenyl and Ar₂ is phenyl or pyridyl,then Y cannot be C₁-C₄ alkylene;

with the further proviso that when Ar₁ and Ar₂ are phenyl, q=1, m andn=0, Y is

and R₃ is H, then R₄ is not C₁-C₆ alkyl;

and the stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt and ester forms thereof.

In an additional embodiment of the invention, there are providedcompounds of formula (I):

wherein Ar₁ and Ar₂ are the same or different and are each selected fromthiophene, isothiazole, phenyl, pyridyl, oxazole, isoxazole, thiazole,imidazole, and other five or six membered heterocycles comprising 1-3atoms of —N—, —O—, or —S—, provided that Ar₁ and Ar₂ are not both phenyland when Ar₁ is phenyl, Ar₂ is not pyridyl; R₁—R₄ are the same ordifferent and are each selected from H, lower alkyl, —OH,—CH(R₆)—CONR_(6A)R_(6B), or any of R₁—R₄ can be taken together to form a3-7 member carbocyclic or heterocyclic ring, provided that R₃ and R₄ arenot both OH; R_(6A)and R_(6B)are independently H or lower alkyl; and nis 0, 1, or 2; and

in addition, each of Ar₁ or Ar₂ may be independently optionallysubstituted with one or more substituents independently selected from:

a) H, aryl, heterocyclyl, F, Cl, Br, I, —CN, —CF₃, —NO₂, —OH, —OR₇,—O(CH₂)_(p)NR₉R₁₀, —OC(═O)R₇, —OC(═O)NR₉R₁₀, —O(CH₂)_(p)OR₈, —CH₂OR₈,—NR₉R₁₀, —NR₈S(═O)₂R₇, —NR₈C(═O)R₇, or —NR₈C(═S)R₇;

b) —CH₂OR₁₁, where R₁₁ is the residue of an amino acid after thehydroxyl group of the carboxyl group is removed;

c) —NR₈C(═O)NR₉R₁₀, —NR₈C(═S)NR₉R₁₀, —CO₂R₁₂, —C(═O)R₁₂, —C(═O)NR₉R₁₀,—C(═S)NR₉R₁₀, —CH═NOR₁₂, —CH═NR₇, —(CH₂)_(p)NR₉R₁₀, —(CH₂)_(p)NHR₁₁, or—CH═NNR₁₂R_(12A), where R₁₂ and R_(12A)are the same or different andeach are independently selected from H, alkyl of 1 to 4 carbons, —OH,alkoxy of 1 to 4 carbons, —OC(═O)R₇, —OC(═O)NR₉R₁₀, —OC(═S)NR₉R₁₀,—O(CH₂)_(p)NR₉R₁₀, —O(CH₂)_(p)OR₈, substituted or unsubstitutedarylalkyl having from 6 to 10 carbons, and substituted or unsubstitutedheterocyclylalkyl;

d) —S(O)_(y)R₁₂, —(CH₂)_(p)S(O)_(y)R₇, —CH₂S(O)_(y)R₁₁ where y is 0, 1or 2; and

e) alkyl of 1 to 8 carbons, alkenyl of 2 to 8 carbons, or alkynyl of 2to 8 carbons, where:

1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or

2) each alkyl, alkenyl or alkynyl group is substituted with 1 to 3groups selected from aryl of 6 to 10 carbons, heterocyclyl, arylalkoxy,heterocycloalkoxy, hydroxylalkoxy, alkyloxy-alkoxy, hydroxyalkylthio,alkoxy-alkylthio, F, Cl, Br, I, —CN, —NO₂, —OH, —OR₇,—X₂(CH₂)_(p)NR₉R₁₀, —X₂(CH₂)_(p)C(═O)NR₉R₁₀, —X₂(CH₂)_(p)C(═S)NR₉R₁₀,—X₂(CH₂)_(p)OC(═O)NR₉R₁₀, —X₂(CH₂)_(p)CO₂R₇, —X₂(CH₂)_(p)S(O)_(y)R₇,—X₂(CH₂)_(p)NR₈C(═O)NR₉R₁₀, —OC(═O)R₇, —OC(═O)NHR₁₂,O-tetrahydropyranyl, —NR₉R₁₀, —NR₈CO₂R₇, —NR₈C(═O)NR₉R₁₀,—NR₈C(═S)NR₉R₁₀, —NHC(═NH)NH₂, —NR₈C(═O)R₇, —NR₈C(═S)R₇, —NR₈S(═O)₂R₇,—S(O)_(y)R₇, —CO₂R₁₂, —C(═O)NR₉R₁₀, —C(═S)NR₉R₁₀, —C(═O)R₁₂, —CH₂OR₈,—CH═NNR₁₂R_(12A), —CH═NOR₁₂, —CH═NR₇, —CH═NNHCH(N═NH)NH₂,—S(═O)₂NR₁₂R_(12A), —P(═O)(OR₈)₂, —OR₁₁, and a monosaccharide of 5 to 7carbons where each hydroxyl group of the monosaccharide is independentlyeither unsubstituted or is replaced by H, alkyl of 1 to 4 carbons,alkylcarbonyloxy of 2 to 5 carbons, or alkoxy of 1 to 4 carbons, whereX₂ is O, S, or NR₈; where

R₇ is substituted or unsubstituted alkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heterocyclyl;

R₈ is H or alkyl having from 1 to 4 carbons;

p is from 1 to 4; and where either

1) R₉ and R₁₀ are each independently H, unsubstituted alkyl of 1 to 4carbons, or substituted alkyl; or

2) R₉ and R₁₀ together form a linking group of the formula—(CH₂)₂—X₁—(CH₂)₂—, wherein X₁ is selected from —O—, —S—, and —CH₂—;

and the stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt and ester forms thereof.

In a preferred embodiment of the invention, there are provided compoundsof formula (I) wherein Ar₁ and Ar₂ are the same or different and areeach selected from thiophene, isothiazole, phenyl, oxazole, isoxazole,thiazole, imidazole, or other five or six membered heterocyclescomprising 1-3 atoms of —N—, —O—, or —S—, provided that Ar₁ and Ar₂ arenot both phenyl; R₁—R₄ are the same or different and are each selectedfrom H, lower alkyl, —OH, —CH(R₆)—CONR_(6A)R_(6B), or any of R₁—R₄ canbe taken together to form a 3-7 member carbocyclic or heterocyclic ring,provided that R₃ and R₄ are not both OH; R_(6A)and R_(6B)areindependently H or lower alkyl; and n is 0, 1, or 2; and in addition,

each of Ar₁ or Ar₂ may be independently optionally substituted with oneor more substituents independently selected from:

a) H, aryl, heterocyclyl, F, Cl, Br, I, —CN, —CF₃, —NO₂, —OH, —OR₇,—O(CH₂)_(p)NR₉R₁₀, —OC(═O)R₇, —OC(═O)NR₉R₁₀, —O(CH₂)_(p)OR₈, —CH₂OR₈,—NR₉R₁₀, —NR₈S(═O)₂R₇, —NR₈C(═O)R₇, or —NR₈C(═S)R₇;

b) —CH₂OR₁₁, where R₁₁ is the residue of an amino acid after thehydroxyl group of the carboxyl group is removed;

c) —NR₈C(═O)NR₉R₁₀, —NR₈C(═S)NR₉R₁₀, —CO₂R₁₂, —C(═O)R₁₂, —C(═O)NR₉R₁₀,—C(═S)NR₉R₁₀, —CH═NOR₁₂, —CH═NR₇, —(CH₂)_(p)NR₉R₁₀, —(CH₂)_(p)NHR₁₁, or—CH═NNR₁₂R_(12A), where R₁₂ and R_(12A)are the same or different andeach are independently selected from H, alkyl of 1 to 4 carbons, —OH,alkoxy of 1 to 4 carbons, —OC(═O)R₇, —OC(═O)NR₉R₁₀, —OC(═S)NR₉R₁₀,—O(CH₂)_(p)NR₉R₁₀, —O(CH₂)_(p)OR₈, substituted or unsubstitutedarylalkyl having from 6 to 10 carbons, and substituted or unsubstitutedheterocyclylalkyl;

d) —S(O)_(y)R₁₂, —(CH₂)_(p)S(O)_(y)R₇, —CH₂S(O)_(y)R₁₁ where y is 0, 1or 2; and

e) alkyl of 1 to 8 carbons, alkenyl of 2 to 8 carbons, or alkynyl of 2to 8 carbons, where:

1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or

2) each alkyl, alkenyl or alkynyl group is substituted with 1 to 3groups selected from aryl of 6 to 10 carbons, heterocyclyl, arylalkoxy,heterocycloalkoxy, hydroxylalkoxy, alkyloxy-alkoxy, hydroxyalkylthio,alkoxy-alkylthio, F, Cl, Br, I, —CN, —NO₂, —OH, —OR₇,—X₂(CH₂)_(p)NR₉R₁₀, —X₂(CH₂)_(p)C(═O)NR₉R₁₀, —X₂(CH₂)_(p)C(═S)NR₉R₁₀,—X₂(CH₂)_(p)OC(═O)NR₉R₁₀, —X₂(CH₂)_(p)CO₂R₇, —X₂(CH₂)_(p)S(O)_(y)R₇,—X₂(CH₂)_(p)NR₈C(═O)NR₉R₁₀, —OC(═O)R₇, —OC(═O)NHR₁₂,O-tetrahydropyranyl, —NR₉R₁₀, —NR₈CO₂R₇, —NR₈C(═O)NR₉R₁₀,—NR₈C(═S)NR₉R₁₀, —NHC(═NH)NH₂, —NR₈C(═O)R₇, —NR₈C(═S)R₇, —NR₈S(═O)₂R₇,—S(O)_(y)R₇, —CO₂R₁₂, —C(═O)NR₉R₁₀, —C(═S)NR₉R₁₀, —C(═O)R₁₂, —CH₂OR₈,—CH═NNR₁₂R_(12A), —CH═NOR₁₂, —CH═NR₇, —CH═NNHCH(N═NH)NH₂,—S(═O)₂NR₁₂R_(12A), —P(═O)(OR₈)₂, —OR₁₁, and a monosaccharide of 5 to 7carbons where each hydroxyl group of the monosaccharide is independentlyeither unsubstituted or is replaced by H, alkyl of 1 to 4 carbons,alkylcarbonyloxy of 2 to 5 carbons, or alkoxy of 1 to 4 carbons, whereX₂ is O, S, or NR₈; where

R₇ is substituted or unsubstituted alkyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heterocyclyl;

R₈ is H or alkyl having from 1 to 4 carbons;

p is from 1 to 4; and where either

1) R₉ and R₁₀ are each independently H, unsubstituted alkyl of 1 to 4carbons, or substituted alkyl; or

2) R₉ and R₁₀ together form a linking group of the formula—(CH₂)₂—X₁—(CH₂)₂—, wherein X₁ is selected from —O—, —S—, and —CH₂—;

and the stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt and ester forms thereof.

In another embodiment of the invention, there is provided novelcompounds of the formula (II-A):

wherein

X is a bond, —CH₂CH₂—, —O—, —S(O)_(y)—, —N(R₈)—, —CHN(R₈)—, —CH═CH—,—CH₂—CH═CH—, C(═O), —C(R₈)═N—, —N═C(R₈)—, —C(═O)—N(R₈)—, or —NR₈—C(═O)—;

Rings A and B, together with the carbon atoms to which they areattached, are each independently selected from:

a) a 6-membered aromatic carbocyclic ring in which from 1 to 3 carbonatoms may be replaced by hetero atoms selected from oxygen, nitrogen andsulfur; and

b) a 5-membered aromatic carbocyclic ring in which either:

i) one carbon atom is replaced with an oxygen, nitrogen, or sulfur atom;

ii) two carbon atoms are replaced with a sulfur and a nitrogen atom, anoxygen and a nitrogen atom, or two nitrogen atoms; or

iii) three carbon atoms are replaced with three nitrogen atoms, oneoxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms;

wherein Ring A and Ring B may each independently be substituted with 1-3substituents selected from:

a) H, C₆-C₁₀ aryl, heteroaryl, F, Cl, Br, I, —CN, —CF₃, —NO₂, —OH, —OR₇,—O(CH₂)_(p)NR₉R₁₀, —OC(═O)R₇, —OC(═O)NR₉R₁₀, —O(CH₂)_(p)OR₈, —CH₂OR₈,—NR₉R₁₀, —NR₈S(═O)₂R₇, —NR₈C(═O)R₇, or —NR₈C(═S)R₇;

b) —CH₂OR₁₁;

c) —NR₈C(═O)NR₈R₁₀, —NR₈C(═S)NR₉R₁₀, —CO₂R₁₂, —C(═O)R₁₃, —C(═O)NR₉R₁₀,—C(═S)NR₉R₁₀, —CH═NOR₁₂, —CH═NR₇, —(CH₂)_(p)NR₉R₁₀, —(CH₂)_(p)NHR₁₁,—CH═NNR₁₂R_(12A), —C(═NR₈)NR_(8A)R_(8B)—NR₈C(═NH)R_(8A),—NR₈C(═NH)NR_(8A)R_(8B),

d) —S(O)_(y)R₇, —(CH₂)_(p)S(O)_(y)R₇, —CH₂S(O)_(y)R₇; and

e) C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-Cg alkynyl, where:

1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or

2) each alkyl, alkenyl or alkynyl group is independently substitutedwith 1 to 3 groups independently selected from C₆-C₁₀ aryl, heteroaryl,F, Cl, Br, I, CF₃, —CN, —NO₂, —OH, —OR₇, —CH₂OR₈, —NR₉R₁₀,—O—(CH₂)_(p)—OH, —S—(CH₂)_(p)—OH, —X₁(CH₂)_(p)OR₇, X₁(CH₂)_(p)NR₉R₁₀,—X₁(CH₂)_(p)C(═O)NR₉R₁₀, —X₁(CH₂)_(p)C(═S)NR₉R₁₀,—X₁(CH₂)_(p)OC(═O)NR₉R₁₀, —X₁(CH₂)_(p)CO₂R₈, —X₁(CH₂)_(p)S(O)_(y)R₇,—X₁(CH₂)_(p)NR₈C(═O)NR₉R₁₀, —C(═O)R₁₃, —CO₂R₁₂, —OC(═O)R₇, —C(═O)NR₉R₁₀,—OC(═O)NR₁₂R_(12A), O-tetrahydropyranyl, —C(═S)NR₉R₁₀, —CH═NNR₁₂R_(12A),—CH═NOR₁₂, —CH═NR₇, —CH═NNHCH(N═NH)NH₂, —NR₈CO₂R₇, —NR₈C(═O)NR₉R₁₀,—NR₈C(═S)NR₉R₁₀, —NHC(═NH)NH₂, —NR₈C(═O)R₇, —NR₈C(═S)R₇, —NR₈S(═O)₂R₇,—S(O)_(y)R₇, —S(═O)₂NR₁₂R_(12A), —P(═O)(OR₈)₂, —OR₁₁, and a C₅-C₇monosaccharide where each hydroxyl group of the monosaccharide isindependently either unsubstituted or is replaced by H, C₁-C₄ alkyl,C₁-C₄ alkoxy, or —O—C(═O)R₇; R₃ and R₄ are the same or different and areeach selected from H, C₁-C₆ alkyl, —OH, —CH(R₆)—CONR_(8A)R_(8B),provided that R₃ and R₄ are not both OH, or R₃ and R₄, together with thenitrogen to which they are attached, form a 3-7 member heterocyclicring;

R₃ and R₄ are the same or different and are each selected from H, C₁-C₆alkyl, —OH, and —CH(R₆)—CONR_(8A)R_(8B), provided that R₃ and R₄ are notboth OH; or R₃ and R₄, together with the nitrogen to which they areattached, form a 3-7 member heterocyclic ring;

R₆ is H, C₁-C₄ alkyl or the side chain of an a-amino acid;

R₇ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or heteroaryl;

R₈, R_(8A)and R_(8B)are each independently H, C₁-C₄ alkyl, or C₆-C₁₀aryl;

R₉ and R₁₀ are independently selected from H, C₁-C₄ alkyl, and C₆-C₁₀aryl; or R₉ and R₁₀ together with the nitrogen to which they areattached, form a 3-7 member heterocyclic ring;

R₁₁ is the residue of an amino acid after the hydroxyl group of thecarboxyl group is removed;

R₁₂ and R_(12A)are each independently selected from H, C₁-C₆ alkyl,cycloalkyl, C₆-C₁₀ aryl, and heteroaryl; or R₁₂ and R_(12A), togetherwith the nitrogen to which they are attached, form a 5-7 memberheterocyclic ring;

R₁₃ is H, C₁-C₆ alkyl, cycloalkyl, C₆-C₁₀ aryl, heteroaryl, —C(═O)R₇,—C(═O)NR₉R₁₀, or —C(═S)NR₉R₁₀;

X₁ is —O—, —S—, —N(R₈)—;

Y is selected from C₁-C₄ alkylene, C₆-C₁₀ arylene, heteroarylene, C₃-C₈cycloalkylene, heterocyclylene, —O—, —N(R₈)—, —S(O)_(y),—CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—, or —C≡C—; with theproviso that when Y is —O—, —N(R₈)—, or —S(O)_(y), m and n cannot be 0;

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

p is from 1 to 4;

q is 0, 1, 2;

t is 2, 3, or 4;

y is 0, 1 or 2;

and the stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt and ester forms thereof.

In a further embodiment, there are provided compounds of formula (II):

where X is —(CH₂)_(m)—, —O—, —S(O)_(n)—, —N(R₅)—, —CH═CH—, or—CH₂—CH═CH—; m is 0, 1, 2 or 3; n is 0, 1 or 2; R₁—R₄ are the same ordifferent and are each selected from H, lower alkyl, —OH,—CH(R₆)—CONR₇R₈, or any of R₁—R₄ can be taken together to form a 3-7member carbocyclic or heterocyclic ring; R₅ is H, lower alkyl, or —OH;R₆, R₇ and R₈ is H or lower alkyl; and ring A, together with the carbonatoms to which it is attached is selected from:

a) a 6-membered carbocyclic ring in which from 1 to 3 carbon atoms maybe replaced by hetero atoms selected from oxygen, nitrogen and sulfur;and

b) a 5-membered carbocyclic ring in which either:

i) one carbon atom may be replaced with an oxygen, nitrogen, or sulfuratom;

ii) two carbon atoms may be replaced with a sulfur and a nitrogen atom,an oxygen and a nitrogen atom, or two nitrogen atoms; or

iii) three carbon atoms may be replaced with three nitrogen atoms, oneoxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms;

and the stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt and ester forms thereof.

As with any group of structurally related compounds which possess aparticular utility, certain groups and configurations are preferred forthe compounds of the present invention in their end-use application.

In some embodiments of formula (I-A) or (II-A), Y≡C(R₁)(R₂), wherein R₁and R₂ are each independently selected from H or C₁-C₆ alkyl; andoptionally, either R₁ or R₂ can combine with either R₃ or R₄ to form a5-7 membered heterocyclic ring. In some particular embodiments, R₁combines with R₃ to form compounds (III) and (IV):

wherein w is 2, 3, or 4.

In certain embodiments of formula (I-A), Ar₁ and Ar₂ are eachindependently selected from a five or six membered heteroaryl comprising1-3 atoms of —N—, —O—, or —S—. Preferably, q=1. In preferredembodiments, Ar₁ and Ar₂ are each independently selected from thienyl,isothiazolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, and imidazolyl,and more preferably, Ar₁ and Ar₂ are thienyl, and particularly Ar₁ andAr₂ are 3-thienyl. In other preferred embodiments, Y is —O—, —S(O)_(y)—,or —N(R₈)—. In another preferred embodiment, Y is C₁-C₄ alkylene. In anadditional embodiment, Y is —CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—,—CH(R₈)—CH═CH—, or —C≡C—. In certain preferred embodiments, Y is C₆-C₁₀arylene or heteroarylene, and preferably, m=0 or 1 and n=0 or 1. Morepreferably, Y is

wherein X₂ is —CH₂—, —O—, —S(O)_(y)—, or —N(R₈)—; and X₃, X₄, and X₅ areeach independently selected from —CH—, or —N—. Most preferably, Y isphenylene. In another more preferred embodiment, Y is

In yet another embodiment, Y is furanylene. In further preferredembodiments, Y is C₃-C₈ cycloalkylene or heterocyclylene. Preferably, Yis

In other embodiments of formula (I-A), Ar₁ is phenyl and Ar₂ is a fiveor six membered heteroaryl comprising 1-3 atoms of —N—, —O—, or —S—.Preferably, q=1. In other preferred embodiments, Ar₁ and Ar₂ are eachindependently phenyl, thienyl, isothiazolyl, pyridyl, oxazolyl,isoxazolyl, thiazolyl, and imidazolyl. In further preferred embodiments,Ar₁ is phenyl and Ar₂ is thienyl, isothiazolyl, pyridyl, oxazolyl,isoxazolyl, thiazolyl, and imidazolyl, and more preferably, Ar₁ isphenyl and Ar₂ is thienyl, and particularly, Ar₂ is 3-thienyl. In otherpreferred embodiments, Y is —O—, —S(O)_(y)—, or —N(R₈)—. In anotherpreferred embodiment, Y is C₁-C₄ alkylene. In an additional embodiment,Y is —CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—, or —C≡C—. Incertain preferred embodiments, Y is C₆-C₁₀ arylene or heteroarylene, andpreferably, m=0 or 1 and n=0 or 1. More preferably, Y is

wherein X₂ is —CH₂—, —O—, —S(O)_(y)—, or —N(R₈)—; and X₃, X₄, and X₅ areeach independently selected from —CH—, or —N—. Most preferably, Y isphenylene. In another more preferred embodiment, Y is

In yet another embodiment, Y is furanylene. In further preferredembodiments, Y is C₃-C₈ cycloalkylene or heterocyclylene. Preferably, Yis

In another embodiment of formula (I-A), Ar₁ and Ar₂ is phenyl.Preferably, q=1. In other preferred embodiments, Y is —O—, —S(O)_(y)—,or —N(R₈)—. In another preferred embodiment, Y is C₁-C₄ alkylene. In anadditional embodiment, Y is —CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—,—CH(R₈)—CH═CH—, or —C≡C—. In certain preferred embodiments, Y is C₆-C₁₀arylene or heteroarylene, and preferably, m=0 or 1 and n=0 or 1. Morepreferably, Y is

wherein X₂ is —CH₂—, —O—, —S(O)_(y)—, or —N(R₈)—; and X₃, X₄, and X₅ areeach independently selected from —CH—, or —N—. Most preferably, Y isphenylene. In another more preferred embodiment, Y is

In yet another embodiment, Y is furanylene. In further preferredembodiments, Y is C₃-C₈ cycloalkylene or heterocyclylene. Preferably, Yis

In an additional embodiment of formula (I-A), Y is —O—, —S(O)_(y)—,—N(R₈)—, C₁-C₄ alkylene, —CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—,—CH(R₈)—CH═CH—, —C≡C—,

wherein X₂ is —CH₂—, —O—, —S(O)_(y)—, or —N(R₈)—; and X₃, X₄, and X₅ areeach independently selected from —CH—, or —N—. In other preferredembodiments, Y is —O—, —S(O)_(y)—, or —N(R₈)—. In another preferredembodiment, Y is C₁-C₄ alkylene. In an additional embodiment, Y is—CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—, or —C═C—. In certainpreferred embodiments, Y is C₆-C₁₀ arylene or heteroarylene, andpreferably, m=0 or 1 and n=0 or 1. More preferably, Y is

wherein X₂ is —CH₂—, —O—, —S(O)_(y)—, or —N(R₈)—; and X₃, X₄, and X₅ areeach independently selected from —CH—, or —N—. Most preferably, Y isphenylene. In another more preferred embodiment, Y is

In yet another embodiment, Y is furanylene. In further preferredembodiments, Y is C₃-C₈ cycloalkylene or heterocyclylene. Preferably, Yis

In yet another embodiment of formula (I-A), q=1.

In a further embodiment of formula (I-A), Ar₁ and Ar₂ are eachindependently selected from phenyl and thienyl, and q=1. Preferably Ar₁and Ar₂ are each independently selected from phenyl and 3-thienyl, andq=1. In other preferred embodiments, Y is —O—, —S(O)_(y)—, or —N(R₈)—.In another preferred embodiment, Y is C₁-C₄ alkylene. In an additionalembodiment, Y is —CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—, or—C≡C—. In certain preferred embodiments, Y is C₆-C₁₀ arylene orheteroarylene, and preferably, m=0 or 1 and n=0 or 1. More preferably, Yis

wherein X₂ is —CH₂—, —O—, —S(O)_(y)—, or —N(R₈)—; and X₃, X₄, and X₅ areeach independently selected from —CH—, or —N—. Most preferably, Y isphenylene. In another more preferred embodiment, Y is

In yet another embodiment, Y is furanylene. In further preferredembodiments, Y is C₃-C₈ cycloalkylene or heterocyclylene. Preferably, Yis

Preferred embodiments of formula (I-A) are compounds wherein Ar₁ and Ar₂are the same or different and are each selected from thiophene,isothiazole, phenyl, pyridyl, oxazole, isoxazole, thiazole, imidazole,provided that Ar₁ and Ar₂ are both not phenyl and when Ar₁ is phenyl,Ar₂ is not pyridyl.

Preferred embodiments of formula (I) are compounds wherein Ar₁ and Ar₂are the same or different and are each selected from thiophene,isothiazole, phenyl, oxazole, isoxazole, thiazole, imidazole, providedthat Ar₁ and Ar₂ are both not phenyl. Other preferred embodiments arethose where Ar₁ and Ar₂ are each independently substituted.

Additional preferred embodiments of formula (I) are given below:

1) Compounds in which Ar₁, Ar₂ or both are thiophene;

2) Compounds in which Ar₁, Ar₂ or both are isothiazole;

3) Compounds in which Ar₁, Ar₂ or both are pyridyl;

4) Compounds in which Ar₁, Ar₂ or both are oxazole;

5) Compounds in which Ar₁, Ar₂ or both are isoxazole;

6) Compounds in which Ar₁, Ar₂ or both are thiazole;

7) Compounds in which Ar₁, Ar₂ or both are imidazole,

8) Compounds in which Ar₁ is phenyl and Ar₂ is thiophene.

In a preferred embodiment of the of formula (I-A), there are providedcompounds as represented in Table 1:

TABLE 1

No. Ar₁ Ar₂ Y m n NR₃R₄ I-1 3-Thienyl 3-Thienyl —CH₂— 1 0 NH₂ I-23-Thienyl 3-Thienyl —CH₂— 1 0 NMe₂ I-3 3-Thienyl 3-Thienyl —CH₂— 2 1 NH₂I-4 3-Thienyl 3-Thienyl —CH₂— 1 0 NHCH(CH₃)—CONH₂ I-5 3-Thienyl3-Thienyl —C(CH₃)₂— 1 0 NH₂ I-6 3-Thienyl 3-Thienyl

1 0 NH₂ I-7 Ph 3-Thienyl

1 0 NH₂ I-8 Ph 3-Thienyl —CH₂— 2 1 NH₂ I-9 3-Thienyl 3-Thienyl —CH₂— 0 0NH₂ I-10 3-Thienyl 3-Thienyl —CH₂— 0 0 NH(C₃H₇) I-11 3-Thienyl 3-Thienyl—CH₂— 0 0 N(CH₃)₂ I-12 3-Thienyl 3-Thienyl —CH₂— 0 0 N(CH₂CH₃)₂ I-133-Thienyl 3-Thienyl —CH₂— 0 0 morpholino I-14 3-Isothiazolyl3-Isothiazolyl —CH₂— 0 0 NH₂ I-15 4-Thiazolyl 4-Thiazolyl —CH₂— 0 0 NH₂I-16 2-Thiazolyl 2-Thiazolyl —CH₂— 0 0 NH₂ I-17 3-Isoxazolyl3-Isoxazolyl —CH₂— 0 0 NH₂ I-18 4-Oxazolyl 4-Oxazolyl —CH₂— 0 0 NH₂ I-192-Oxazolyl 2-Oxazolyl —CH₂— 0 0 NH₂ I-20 4-Imidazolyl 4-Imidazolyl —CH₂—0 0 NH₂ I-21 2-Imidazolyl 2-Imidazolyl —CH₂— 0 0 NH₂ I-22 Phenyl3-Thienyl —CH₂— 0 0 NH₂ I-23 2-Pyridyl 2-Pyridyl —CH₂— 0 0 NH₂ I-243-Pyridyl 3-Pyridyl —CH₂— 0 0 NH₂ I-25 4-Pyridyl 4-Pyridyl —CH₂— 0 0 NH₂I-26 3-Thienyl 3-Thienyl —CH₂— 0 0 NH(CH₂)₂OH I-27 3-Thienyl 3-Thienyl—CH₂— 0 0 NH(CH₂)₂-N-piperidyl I-28 3-Thienyl 3-Thienyl —CH₂— 0 0NH(CH₂)₂-N-morpholinoyl I-29 3-Thienyl 3-Thienyl —CH₂— 0 0 NH(CH₃) I-303-Thienyl 3-Thienyl —CH₂— 0 0 NH(CH₂-[2-pyridyl]) I-31 3-Thienyl3-Thienyl —CH₂— 0 0 NH(CH₂-[3-pyridyl]) I-32 3-Thienyl 3-Thienyl —CH₂— 00 NH(CH₂-[4-pyridyl]) I-33 3-Thienyl 3-Thienyl —CH₂— 0 0

I-34 3-Thienyl 3-Thienyl —CH₂— 0 0

I-35 3-Thienyl 3-Thienyl

1 0 NH₂ I-36 Phenyl 3-Thienyl —CH₂— 1 0 NH₂ I-37 2-Thiazolyl Phenyl—CH₂— 0 0 NH₂ I-38 2-Thiazolyl 2-Thienyl —CH₂— 0 0 NH₂

In certain preferred embodiments of the present invention, there areprovided compounds of formula (II) or (II-A) where q=1.

In another embodiment of formula (II-A), X is a bond, —CH₂CH₂—, —O—,—N(CH₃)—, or —CH═CH—, and preferably X is a bond.

In certain embodiments of formula (II-A), Y is —O—, —S(O)_(y), —N(R₈)—,C₁-C₄ alkylene, —CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—,—C≡C—,

wherein X₂ is —CH₂—, —O—, —S(O)_(y)—, or —N(R₈)—; and X₃, X₄, and X₅ areeach independently selected from —CH—, or —N—. In other preferredembodiments, Y is —O—, —S(O)_(y)—, or —N(R₈)—. In another preferredembodiment, Y is C₁-C₄ alkylene. In an additional embodiment, Y is—CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—, or —C≡C—. In certainpreferred embodiments, Y is C₆-C₁₀ arylene or heteroarylene, andpreferably, m=0 or 1 and n=0 or 1. More preferably, Y is

wherein X₂ is —CH₂—, —O—, —S(O)_(y)—, or —N(R₈)—; and X₃, X₄, and X₅ areeach independently selected from —CH—, or —N—. Most preferably, Y isphenylene. In another more preferred embodiment, Y is

In further preferred embodiments, Y is C₃-C₈ cycloalkylene orheterocyclylene. Preferably, Y is

In additional embodiments of formula (II-A), rings A and B, togetherwith the carbon atoms to which they are attached, are each independentlyselected from phenylene, thienylene, isothiazolylene, pyridylene,oxazolylene, isoxazolylene, thiazolylene, imidazolylene. In a preferredembodiment, ring A is phenylene, and more preferably, rings A and B arephenylene. In another preferred embodiment, rings A and B arethienylene, and more preferably, rings A and B are 2,3-thienylene. Inpreferred embodiments, q=1. In further preferred embodiments, ring A isphenylene and ring B is 2,3-thienylene. In other preferred embodiments,X is a bond, —CH₂CH₂—, —O—, —N(CH₃)—, or —CH═CH—. In a more preferredembodiment, Y is —O—, —S(O)_(y)—, —N(R₈)—, C₁-C₄ alkylene,—CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—, —C≡C—,

wherein X₂ is —CH₂—, —O—, —S(O)_(y)—, or —N(R₈)—, and X₃, X₄, and X₅ areeach independently selected from —CH—, or —N—. In other preferredembodiments, Y is —O—, —S(O)_(y)—, or —N(R₈)—. In another preferredembodiment, Y is C₁-C₄ alkylene. In an additional embodiment, Y is—CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—, or —C≡C—. In certainpreferred embodiments, Y is C₆-C₁₀ arylene or heteroarylene, andpreferably, m=0 or 1 and n=0 or 1. More preferably, Y is

wherein X₂ is —CH₂—, —O—, —S(O)_(y)—, or —N(R₈)—; and X₃, X₄, and X₅ areeach independently selected from —CH—, or —N—. Most preferably, Y isphenylene. In another more preferred embodiment, Y is

In further preferred embodiments, Y is C₃-Cg cycloalkylene orheterocyclylene. Preferably, Y is

In an especially preferred embodiment, X is a bond, and Y is —CH₂— andn=0.

Preferred embodiments of formula (II) are compounds wherein ring A isselected from thiophene, isothiazole, phenyl, oxazole, isoxazole,thiazole, and imidazole. Other preferred embodiments are those where thebenzo ring and ring A are each independently substituted.

Other preferred embodiments of formula (II) are given below:

1) Compounds in which A is benzo and X is a bond, i.e. —(CH₂)_(m)—,where m=0;

2) Compounds in which A is benzo and X is —O—;

3) Compounds in which A is benzo and X is —NCH_(3;)

4) Compounds in which A is benzo and X is —S—; and

5) Compounds in which R₃ and R₄ are taken together with the nitrogen towhich they are attached to form a morpholine ring.

In a particularly preferred embodiment of formula (II-A), there areprovided compounds as represented in Table 2:

TABLE 2 (II-A)

No. A B X Y m n NR₃R₄ II-1 Bnezo Benzo bond —CH₂— 1 0 NH₂ II-2 BenzoBenzo bond —CH₂— 1 0 NMe₂ II-3 Benzo Benzo bond —CH₂— 1 1 NH₂ II-4 BenzoBenzo bond —CH₂— 1 0 NHCH(CH₃)—CONH₂ II-5 Benzo Benzo bond —CH₂— 1 0morpholino II-6 Benzo Benzo bond —CH₂— 2 1 NH₂ II-7 Benzo Benzo bond—CH₂— 2 1 NMe₂ II-8 Benzo Benzo bond —CH(CH₃)— 1 0 NH₂ II-9 Benzo Benzobond —CH₂— 0 0 NHCH(CH₃)—CONH₂ II-10 Benzo Benzo bond

1 0 NH₂ II-11 Benzo Benzo bond —C(CH₃)₂— 1 0 NH₂ II-12 Benzo Benzo bond

1 0 NH₂ II-13 Benzo Benzo —CH₂CH₂— —CH₂— 1 0 NH₂ II-14 Benzo Benzo—CH₂CH₂— —CH(CH₃)— 1 0 NH₂ II-15 Benzo Benzo bond

1 0 NH₂ II-16 Benzo Benzo bond

1 0 NH₂ II-17 Benzo Benzo bond

1 0 NMe₂ II-18 Benzo Benzo —CH═CH— —CH₂— 2 1 NH₂ II-19 Benzo Benzo—CH═CH— —C(CH₃)₂— 1 0 NH₂ II-20 Benzo Benzo —O— —CH₂— 2 1 NH₂ II-21Benzo Benzo —O— —CH(CH₃)— 1 0 NH₂ II-22 2,3-Thieno 2,3-Thieno bond —CH₂—0 0 NH₂ II-23 Benzo Benzo bond —CH₂— 0 0 NH₂ II-24 Benzo Benzo bond—CH₂— 0 0 NHCH(CH₃)—CONMe₂ II-25 Benzo Benzo —CH₂CH₂— —CH₂— 0 0 NH₂II-26 Benzo Benzo —CH₂CH₂— —CH₂— 0 0 N(CH₃)₂ II-27 Benzo Benzo —O— —CH₂—0 0 NH₂ II-28 Benzo Benzo —N(CH₃)— —CH₂— 0 0 NH₂ II-29 Benzo Benzo —S——CH₂— 0 0 NH₂ II-30 Benzo Benzo bond —CH₂— 0 0 NH(CH₃) II-31 Benzo Benzobond —CH₂— 0 0 NH(CH₂CH₂—NH[t-Boc]) II-32 Benzo Benzo bond —CH₂— 0 0NH(CH₂-[2-pyridyl]) II-33 Benzo Benzo bond —CH₂— 0 0 NH(CH₂-[3-pyridyl])II-34 Benzo Benzo bond —CH₂— 0 0 NH(CH₂CH₂OH) II-35 Benzo Benzo bond—CH₂— 0 0 N(CH₃)₂ II-36 Benzo Benzo bond —CH₂— 0 0

II-37 Benzo Benzo —CH═CH— —CH₂— 0 0 NH₂ II-38 Benzo Benzo bond

1 0 N(CH₃)₂ II-39 Benzo Benzo bond —CH₂— 0 0 NHOH II-40 Benzo Benzo bond—CH₂— 0 0 NHCH₂CONH₂ II-41 Benzo Benzo bond —CH₂— 0 0 NH(CH₂)₂—CONH₂II-42 Benzo Benzo bond —CH₂— 0 0 NH(CH₂)₂F II-43 Benzo Benzo bond —CH₂—0 0 NEt₂ II-44 Benzo Benzo bond —CH₂— 0 0 NH—(R)—CH(CH₃)CONH₂ II-45Benzo Benzo bond —CH₂— 0 0 NH—(R)—CH(CH₃)—C₆H₅ II-46 Benzo Benzo bond—CH₂— 0 0 NH—(S)—CH(CH₃)—CH₂OH II-47 Benzo Benzo bond —CH₂— 0 0NH—(S)—CH(CH₃)—CO₂Me II-48 Benzo Benzo bond —CH₂— 0 0NH—(S)—CH(CH₃)CONH₂ II-49 Benzo Benzo bond —CH₂— 0 0 NH—(S)—CH(CH₃)CONH₂II-50 Benzo Benzo bond —CH₂— 0 0 NH—(S)—CH(CH₃)CONMe₂ II-51 Benzo Benzobond —CH₂— 0 0 NH—(S)—CH(CH₂OH)CONH₂ II-52 Benzo Benzo bond —CH₂— 0 0NH—(S)—CH[CH(OH)CH₃]CONH₂ II-53 Benzo Benzo bond —CH₂— 0 0

II-54 Benzo Benzo bond —CH(CH₃)— 0 0 NH₂ II-55 Benzo Benzo —O— —CH₂— 1 0NH₂ II-56 Benzo Benzo —O— —CH₂— 0 0 N(CH₃)₂ II-57 Benzo Benzo —O— —CH₂—0 0 NH—(S)—CH(CH₃)CONH₂ II-58 Benzo Benzo —CH₂CH₂— —CH₂CH₂— 0 0 NH₂II-59 Benzo Benzo —CH₂CH₂— —CH(CH₃)— 1 0 NH₂ II-60 Benzo Benzo bond

0 0 NH₂ II-61 Benzo Benzo —CH═CH— —C(CH₃)₂— 1 0 NH₂ II-62 Benzo Benzo—CH₂CH₂— —CH₂— 1 0 NH—CH(CH₃)CONH₂ II-63 Benzo Benzo —CH₂CH₂— —CH₂— 1 0morpholino II-64 Benzo Benzo bond

1 0 NH₂ II-65 Benzo Benzo bond —CH═CH— 0 0 NH₂ II-66

Benzo bond —CH₂— 0 0 NH₂

For example, compounds II-1 and II-22 have the following structures:

In additional embodiments of the present invention, there are providedcompounds of formula (V):

wherein:

Ar₁ and Ar₂ are each independently selected from C₆-C₁₀ aryl orheteroaryl;

wherein each of Ar₁ or Ar₂ may be independently optionally substitutedwith 1-3 substituents independently selected from:

a) H, C₆-C₁₀ aryl, heteroaryl, F, Cl, Br, I, —CN, —CF₃, —NO₂, —OH, —OR₇,—O(CH₂)_(p)NR₉R₁₀, —OC(═O)R₇, —OC(═O)NR₉R₁₀, —O(CH₂)_(p)OR₈, —CH₂OR₈,—NR₉R₁₀, —NR₈S(═O)₂R₇, —NR₈C(═O)R₇, or —NR₈C(═S)R₇;

b) —CH₂OR₁₁;

c) —NR₈C(═O)NR₉R₁₀, —NR₈C(═S)NR₉R₁₀, —CO₂R₁₂, —C(═O)R₁₃, —C(═O)NR₉R₁₀,—C(═S)NR₉R₁₀, —CH═NOR₁₂, —CH═NR₇, —(CH₂)_(p)NR₉R₁₀, —(CH₂)_(p)NHR₁₁,—CH═NNR₁₂R_(12A), —C(═NR₈)NR_(8A)R_(8B)—NR₈C(═NH)R_(8A),NR₈C(═NH)NR_(8A)R_(8B),

d) —S(O)_(y)R₇, —(CH₂)_(p)S(O)_(y)R₇, —CH₂S(O)_(y)R₇; and

e) C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, where:

3) each alkyl, alkenyl, or alkynyl group is unsubstituted; or

4) each alkyl, alkenyl or alkynyl group is independently substitutedwith 1 to 3 groups independently selected from C₆-C₁₀ aryl, heteroaryl,F, Cl, Br, I, CF₃, —CN, —NO₂, —OH, —OR₇, —CH₂OR₈, —NR₉R₁₀,—O—(CH₂)_(p)—OH, —S—(CH₂)_(p)—OH, —X₁(CH₂)_(p)OR₇, X₁(CH₂)_(p)NR₉R₁₀,—X₁(CH₂)_(p)C(═O)NR₉R₁₀, —X₁(CH₂)_(p)C(═S)NR₉R₁₀,—X₁(CH₂)_(p)OC(═O)NR₉R₁₀, —X₁(CH₂)_(p)CO₂R₈, —X₁(CH₂)_(p)S(O)_(y)R₇,—X₁(CH₂)_(p)NR₈C(═O)NR₉R₁₀, —C(═O)R₁₃, —CO₂R₁₂, —OC(═O)R₇, —C(═O)NR₉R₁₀,—OC(═O)NR₁₂R_(12A), O-tetrahydropyranyl, —C(═S)NR₉R₁₀, —CH═NNR₁₂R_(12A),—CH═NOR₁₂, —CH═NR₇, —CH═NNHCH(N═NH)NH₂, —NR₈CO₂R₇, —NR₈C(═O)NR₉R₁₀,—NR₈C(═S)NR₉R₁₀, —NHC(═NH)NH₂, —NR₈C(═O)R₇, —NR₈C(═S)R₇, —NR₈S(═O)₂R₇,—S(O)_(y)R₇, —S(═O)₂NR₁₂R_(12A), —P(═O)(OR₈)₂, —OR₁₁, and a C₅-C₇monosaccharide where each hydroxyl group of the monosaccharide isindependently either unsubstituted or is replaced by H, C₁-C₄ alkyl,C₁-C₄ alkoxy, or —O—C(═O)R₇;

X₁ is —O—, —S—, —N(R₈)—;

J is C₂-C₄ alkylene or Q—CO—;

Q is C₁-C₃ alkylene;

R_(2A) is H, C₁-C₆ alkyl, aryl or heteroaryl;

R_(4A) is H, C₁-C₆ alkyl, aryl or heteroaryl;

R₇ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or heteroaryl;

R₈, R_(8A) and R_(8B)are each independently H, C₁-C₄ alkyl, or C₆-C₁₀aryl;

R₉ and R₁₀ are independently selected from H, C₁-C₄ alkyl, and C₆-C₁₀aryl; or R₉ and R₁₀ together with the nitrogen to which they areattached, form a 3-7 member heterocyclic ring;

R₁₁ is the residue of an amino acid after the hydroxyl group of thecarboxyl group is removed;

R₁₂ and R_(12A)are each independently selected from H, C₁-C₆ alkyl,cycloalkyl, C₆-C₁₀ aryl, and heteroaryl; or R₁₂ and R_(12A), togetherwith the nitrogen to which they are attached, form a 5-7 memberheterocyclic ring;

R₁₃ is H, C₁-C₆ alkyl, cycloalkyl, C₆-C₁₀ aryl, heteroaryl, —C(═O)R₇,—C(═O)NR₉R₁₀, or —C(═S)NR₈R₁₀;

p is from 1, 2, 3, or 4;

q is 0, 1, or 2;

t is 2, 3, or 4;

y is 0, 1 or 2;

and the stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt and ester forms thereof.

In particular embodiments of formula (V), Ar₁ and Ar₂ are eachindependently phenyl or thienyl, preferably both are phenyl; q ispreferably 1; when J is C₂-C₄ alkylene, it is preferably C₂ alkylene orC₃ alkylene; R_(2A) is preferably H, C₁-C₆ alkyl and R_(4A) ispreferably phenyl, thienyl or pyridyl, and more preferably, R_(4A) isphenyl.

In another particular embodiment of formula (V), there are providedcompounds where q is 1; and J is Q—CO to form a compound of formula(VI):

wherein Q is C₁-C₃ alkylene. In certain embodiments, Ar₁ and Ar₂ areeach independently phenyl or thienyl, preferably both are phenyl; and Qis C, alkylene or C₂ alkylene. Certain preferred embodiments of formula(VI) are provided in Table 2A:

TABLE 2A (VI)

No. Ar₁ Ar₂ R_(2A) Q R_(4A) VI-1 Phenyl Phenyl H CH₂ H VI-2 PhenylPhenyl H CH₂ CH₃ VI-3 Phenyl Phenyl H CH₂ (CH₂)₂OMe VI-4 Phenyl Phenyl HCH₂ (CH₂)₂OH VI-5 Phenyl Phenyl H CH₂ (S)—CH(CH₃)CH₂OH VI-6 4-Fluoro-4-Fluoro- H CH₂ CH₃ phenyl phenyl VI-7 3-Thienyl 3-Thienyl H CH₂ H VI-83-Thienyl Phenyl H CH₂ H VI-9 Phenyl Phenyl H (CH₂)₂ H

In additional embodiments of the present invention, there are providedcompounds of formula (VII):

wherein

X is a bond, —CH₂CH₂—, —O—, —S(O)_(y)—, —N(R₈)—, —CHN(R₈)—, —CH═CH—,—CH₂—CH═CH—, C(═O), —C(R₈)═N—, —N═C(R₈)—, —C(═O)—N(R₈)—, or —NR₈—C(═O)—;

Rings A and B, together with the carbon atoms to which they areattached, are each independently selected from:

a) a 6-membered aromatic carbocyclic ring in which from 1 to 3 carbonatoms may be replaced by hetero atoms selected from oxygen, nitrogen andsulfur; and

b) a 5-membered aromatic carbocyclic ring in which either:

i) one carbon atom is replaced with an oxygen, nitrogen, or sulfur atom;

ii) two carbon atoms are replaced with a sulfur and a nitrogen atom, anoxygen and a nitrogen atom, or two nitrogen atoms; or

iii) three carbon atoms are replaced with three nitrogen atoms, oneoxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms;

wherein Ring A and Ring B may each independently be substituted with 1-3substituents selected from:

a) H, C₆-C₁₀ aryl, heteroaryl, F, Cl, Br, I, —CN, —CF₃, —NO₂, —OH, —OR₇,—O(CH₂)_(p)NR₉R₁₀, —OC(═O)R₇, —OC(═O)NR₉R₁₀, —O(CH₂)_(p)OR₈, —CH₂OR₈,—NR₉R₁₀, —NR₈S(═O)₂R₇, —NR₈C(═O)R₇, or —NR₈C(═S)R₇;

b) —CH₂OR₁₁;

c) —NR₈C(═O)NR₉R₁₀, —NR₈C(═S)NR₉R₁₀, —CO₂R₁₂, —C(═O)R₁₃, —C(═O)NR₉R₁₀,—C(═S)NR₉R₁₀, —CH═NOR₁₂, —CH═NR₇, —(CH₂)_(p)NR₉R₁₀, —(CH₂)_(p)NHR₁₁,—CH═NNR₁₂R_(12A), —C(═NR₈)NR_(8A)R_(8B)—NR₈C(═NH)R_(8A),—NR₈C(═NH)NR_(8A)R_(8B),

d) —S(O)_(y)R₇, —(CH₂)_(p)S(O)_(y)R₇, —CH₂S(O)_(y)R₇; and

e) C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, where:

1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or

2) each alkyl, alkenyl or alkynyl group is independently substitutedwith 1 to 3 groups independently selected from C₆-C₁₀ aryl, heteroaryl,F, Cl, Br, I, CF₃, —CN, —NO₂, —OH, —OR₇, —CH₂OR₈, —NR₉R₁₀,—O—(CH₂)_(p)—OH, —S—(CH₂)_(p)—OH, —X₁(CH₂)_(p)OR₇, X₁(CH₂)_(p)NR₉R₁₀,—X₁(CH₂)_(p)C(═O)NR₉R₁₀, —X₁(CH₂)_(p)C(═S)NR₉R₁₀,—X₁(CH₂)_(p)OC(═O)NR₉R₁₀, —X, (CH₂)_(p)CO₂R₈, —X₁(CH₂)_(p)S(O)_(y)R₇,—X₁(CH₂)_(p)NR₈C(═O)NR₉R₁₀, —C(═O)R₁₃, —CO₂R₁₂, —OC(═O)R₇, —C(═O)NR₉R₁₀,—OC(═O)NR₁₂R_(12A), O-tetrahydropyranyl, —C(═S)NR₉R₁₀, —CH═NNR₁₂R_(12A),—CH═NOR₁₂, —CH═NR₇, —CH═NNHCH(N═NH)NH₂, —NR₈CO₂R₇, —NR₈C(═O)NR₉R₁₀,—NR₈C(═S)NR₉R₁₀, —NHC(═NH)NH₂, —NR₈C(═O)R₇, —NR₈C(═S)R₇, —NR₈S(═O)₂R₇,—S(O)_(y)R₇, —S(═O)₂NR₁₂R_(12A), —P(═O)(OR₈)₂, —OR₁₁, and a C₅-C₇monosaccharide where each hydroxyl group of the monosaccharide isindependently either unsubstituted or is replaced by H, C₁-C₄ alkyl,C₁-C₄ alkoxy, or —O—C(═O)R₇;

J is C₂-C₄ alkylene or Q—CO—;

Q is C₁-C₃ alkylene;

R_(2A) is H, C₁-C₆ alkyl, aryl or heteroaryl;

R_(4A) is H, C₁-C₆ alkyl, aryl or heteroaryl;

R₇ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or heteroaryl;

R₈, R_(8A)and R_(8B)are each independently H, C₁-C₄ alkyl, or C₆-C₁₀aryl;

R₉ and R₁₀ are independently selected from H, C₁-C₄ alkyl, and C₆-C₁₀aryl; or R₉ and R₁₀ together with the nitrogen to which they areattached, form a 3-7 member heterocyclic ring;

R₁₁ is the residue of an amino acid after the hydroxyl group of thecarboxyl group is removed;

R₁₂ and R_(12A)are each independently selected from H, C₁-C₆ alkyl,cycloalkyl, C₆-C₁₀ aryl, and heteroaryl; or R₁₂ and R_(12A), togetherwith the nitrogen to which they are attached, form a 5-7 memberheterocyclic ring;

R₁₃ is H, C₁-C₆ alkyl, cycloalkyl, C₆-C₁₀ aryl, heteroaryl, —C(═O)R₇,—C(═O)NR₉R₁₀, or —C(═S)NR₉R₁₀;

X₁ is —O—, —S—, —N(R)—;

p is from 1 to 4;

q is 0, 1, or 2;

t is 2, 3, or 4;

y is 0, 1 or 2;

and the stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt and ester forms thereof.

In particular embodiments of formula (VII), rings A and B are eachindependently benzo or thieno, preferably both are benzo; q ispreferably 1; when J is C₂-C₄ alkylene, it is preferably C₂ alkylene orC₃ alkylene; R_(2A) is preferably H, C₁-C₆ alkyl and R_(4A) ispreferably phenyl, thienyl or pyridyl, and more preferably, R_(4A) isphenyl. A preferred embodiment is a compound of formula (VII-1):

In another particular embodiment of formula (VII), there are providedcompounds where q is 1; and J is Q—CO— to form a compound of formula(VIII):

wherein Q is C₁-C₃ alkylene. In certain embodiments, rings A and B areboth preferably benzo; X is preferably a bond or —O—; and Q is Clalkylene or C₂ alkylene. Certain preferred embodiments of formula (VIII)are provided in Table 2B:

TABLE 2B (VIII)

No. A B X R_(2A) Q R_(4A) VIII- Ben- Benzo bond H CH₂ H 1 zo VIII- Ben-Benzo bond H CH₂ Me 2 zo VIII- Ben- Benzo bond H CH₂ (CH₂)₂OMe 3 zoVIII- Ben- Benzo bond H CH₂ (CH₂)₂OH 4 zo VIII- Ben- Benzo bond H CH₂CH(CH₃)CH₂OH 5 zo VIII- Ben- Benzo bond H CH₂ OH 6 zo VIII- Ben- Benzobond H CH₂ CH₂-(4-methoxyphenyl) 7 zo VIII- Ben- Benzo bond H CH₂ Ph 8zo VIII- Ben- Benzo bond H (CH₂)₂ H 9 zo

Definitions

As used herein, the term “alkyl” refers to a substituted orunsubstituted, branched or straight hydrocarbon chain of 1 to 8 carbonatoms, which is formed by the removal of one hydrogen atom. In certainpreferred embodiments, the alkyl group contains from 1 to 6 carbonatoms. In other preferred embodiments, the alkyl group contains from 1to 4 carbon atoms. A designation such as “C₁-C₄ alkyl” refers to analkyl radical containing from 1 to 4 carbon atoms. Examples includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, pentyl, 2-methylpentyl, hexyl, 2-methylhexyl,2,3-dimethylhexyl, heptyl, octyl, etc.

As used herein, the term “lower alkyl,” refers to a C₁ to C₆ saturatedstraight chain, branched, or cyclic hydrocarbon, which are optionallysubstituted. Lower alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl,cyclopentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclohexyl,3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl and the like.

As used herein, “alkenyl” refers to a substituted or unsubstituted,straight or branched hydrocarbon chain containing from 2 to 8 carbonatoms having one or more carbon—carbon double bonds which may occur inany stable point along the chain, and which is formed by removal of onehydrogen atom. A designation “C₂-C₈ alkenyl” refers to an alkenylradical containing from 2 to 8 carbon atoms. Examples include ethenyl,propenyl, isopropenyl, 2,4-pentadienyl, etc.

As used herein, “alkynyl” refers to a substituted or unsubstituted,straight or branched hydrocarbon radical containing from 2 to 8 carbonatoms, having one or more carbon—carbon triple bonds which may occur inany stable point along the chain, and which is formed by removal of onehydrogen atom. A designation “C₂-Cg alkynyl” refers to an alkynylradical containing from 2 to 8 carbon atoms. Examples include ethynyl,propynyl, isopropynyl, 3,5-hexadiynyl, etc.

As used herein, “carbocycle” or “carbocyclic” refer to a substituted orunsubstituted, stable monocyclic or bicyclic hydrocarbon ring which issaturated, partially unsaturated or unsaturated, and contains from 3 to10 carbon atoms. Accordingly the carbocyclic group may be aromatic ornon-aromatic. The bonds connecting the endocyclic carbon atoms of acarbocyclic group may be single, double, triple, or part of a fusedaromatic moiety. Carbocycles are intended to include the “cycloalkyl”and “aryl” compounds defined herein.

As used herein, the term “cycloalkyl” refers to a substituted orunsubstituted hydrocarbon ring of 3 to 7 carbon atoms formed by theremoval of one hydrogen atom. A designation such as “C₅-C₇ cycloalkyl”refers to a cycloalkyl radical containing from 5 to 7 carbon atoms.Examples include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

As used herein, the terms “heterocycle” or “heterocyclic” refer to asubstituted or unsubstituted, saturated, partially unsaturated orunsaturated, stable 3 to 10 membered monocyclic or bicyclic ring whereinat least one member of the ring is a hetero atom. Accordingly theheterocyclic group may be aromatic or non-aromatic. Typically,heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur,selenium, and phosphorus atoms. Preferable heteroatoms are oxygen,nitrogen and sulfur. The nitrogen and sulfur heteroatoms may beoptionally oxidized, and the nitrogen may be optionally substituted innon-aromatic rings. The bonds connecting the endocyclic atoms of aheterocyclic group may be single, double, triple, or part of a fusedaromatic moiety. Heterocycles are intended to include “heterocyclyl” and“heteroaryl” compounds defined herein.

As used herein, “heterocyclyl” refers to a substituted or unsubstituted,saturated, or partially unsaturated, stable 3 to 7 membered heterocyclicring which is formed by removal of one hydrogen atom. Examples includeepoxyethyl, pyrrolidyl, pyrazolidinyl, piperidyl, pyranyl, oxazolinyl,morpholino, morpholinyl, piperazinyl, etc.

Examples of heterocycles include, but are not limited to,2-pyrrolidinyl, 2H-pyrrolyl, 4-piperidinyl, 6H-1,2,5-thiadiazinyl,2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl,pteridinyl, piperidonyl, 4-piperidinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andtetrazole. Suitable heterocycles are also disclosed in The Handbook ofChemistry and Physics, 76th Edition, CRC Press, Inc., 1995-1996, pages2-25 to 2-26, the disclosure of which is hereby incorporated byreference.

Preferred heterocyclic groups formed with a nitrogen atom include, butare not limited to, pyrrolidinyl, piperidinyl, piperidino, morpholinyl,morpholino, thiomorpholino, N-methylpiperazinyl, indolyl, isoindolyl,imidazole, imidazoline, oxazoline, oxazole, triazole, thiazoline,thiazole, isothiazole, thiadiazoles, triazines, isoxazole, oxindole,indoxyl, pyrazole, pyrazolone, pyrimidine, pyrazine, quinoline,iosquinoline, and tetrazole groups.

Preferred heterocyclic groups formed with an oxygen atom include, butare not limited to, furan, tetrahydrofuran, pyran, benzofurans,isobenzofurans, and tetrahydropyran groups. Preferred heterocyclicgroups formed with a sulfur atom include, but are not limited to,thiophene, thianaphthene, tetrahydrothiophene, tetrahydrothiapyran, andbenzothiophenes.

Preferred aromatic heterocyclic groups include, but are not limited to,pyridyl, pyrimidyl, pyrrolyl, furyl, thienyl, imidazolyl, triazolyl,tetrazolyl, quinolyl, isoquinolyl, benzoimidazolyl, thiazolyl,pyrazolyl, and benzothiazolyl groups.

As used herein, the term “substituted” refers to replacement of one ormore hydrogen atoms on an indicated group with a selected group referredto herein as a “substituent”, provided that the substituted atom'svalency is not exceeded, and that the substitution results in a stablecompound. A substituted group has 1 to 5, preferably 1 to 3, and morepreferably 1, independently selected substituents. Preferredsubstituents include, but are not limited to F, Cl, Br, I, OH, OR, NH₂,NR₂, NHOH, NO₂, CN, CF₃, CF₂CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, heterocyclyl, C₆-C₁₀ aryl,heteroaryl, arylalkyl, C(═O)R, COOH, CO₂R, O—C(═O)R, C(═O)NRR′,NRC(═O)R′, NRCO₂R′, OC(═O)NRR′, —NRC(═O)NRR′, —NRC(═S)NRR′, and—SO₂NRR′, wherein R and R′ are each independently hydrogen, C₁-C₆ alkyl,or C₆-C₁₀ aryl.

As used herein, the term “aryl” refers to a substituted orunsubstituted, aromatic carbocyclic ring containing from 6 to 10 carbonatoms, which is formed by removal of one hydrogen atom. Examples includephenyl, naphthyl, indenyl, etc.

As used herein, the term “heteroaryl” refers to a substituted orunsubstituted 5 to 10 membered aromatic heterocyclic ring, which isformed by removal of one hydrogen atom. Examples include pyrrolyl,pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl,purinyl, imidazolyl, thienyl, thiazolyl, benzothiazolyl, furanyl,benzofuranyl, 1,2,4-thiadiazolyl, isothiazolyl, triazoyl, tetrazolyl,isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, carbazolyl,benzimidazolyl, isoxazolyl, etc.

As used herein, the term “alkylene” refers to a substituted orunsubstituted, branched or straight chained hydrocarbon of 1 to 8 carbonatoms, which is formed by the removal of two hydrogen atoms. Adesignation such as “C₁-C₄ alkylene” refers to an alkylene radicalcontaining from 1 to 4 carbon atoms. Examples include methylene (—CH₂—),propylidene (CH₃CH₂CH═), 1,2-ethandiyl (—CH₂CH₂—), etc.

As used herein, the term “cycloalkylene” refers to substituted orunsubstituted carbocyclic ring of 3 to 8 carbon atoms, which is formedby removal of two hydrogen atoms. A designation such as “C₃-C₈cycloalkylene” refers to an cycloalkylene radical containing from 3 to 8carbon atoms. Examples include cyclopropylene (—C₃H₄—), cyclopentylene(—C₅H₈—), cyclohexylene (—C₆H₁₀—), etc.

As used herein, the term “heterocyclylene” refers to a substituted orunsubstituted, saturated, or partially unsaturated, stable 3 to 7membered heterocyclic ring, which is formed by removal of two hydrogenatoms. Examples include epoxyethylene, pyrrolidylene, pyrrolidylidene,pyrazolidinylene, piperidylene, pyranylene, morpholinylidene, etc.

As used herein, the term “arylene” refers to a substituted orunsubstituted aromatic carbocyclic ring containing from 6 to 10 carbonatoms, which is formed by removal of two hydrogen atoms. Examplesinclude phenylene (—C₆H₄—), naphthylene (—C₁₀H₆—), etc. The “phenylene”group has the following structure:

As used herein, the term “heteroarylene” refers to a substituted orunsubstituted 5 to 10 membered aromatic heterocyclic ring formed byremoval of two hydrogen atoms. Examples include the heteroarylene groupswhich correspond to the respective heteroaryl compounds described above,and in particular, include thienylene (—C₄H₂S—), pyridylene (—C₅H₃N—),pyrimidinylene (—C₃H₂N₂—), quinolinylene (—C₉H₅N—), thiazolylene(—C₃HNS—), etc. The “thienylene” group has the following structure:

The “pyridylene” group has the following structure:

As used herein, the term “alkoxy” refers to an oxygen radicalsubstituted with an alkyl group. Preferably, the alkoxy group containsfrom 1 to 6 carbon atoms. A designation such as “C₁-C₄ alkoxy” refers toan alkoxy containing from 1 to 4 carbon atoms. Examples include methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,t-butoxy, etc.

As used herein, the term “arylalkyl” refers to an aryl-substituted alkylgroup and includes benzyl, bromobenzyl, diphenylmethyl, triphenylmethyl,phenylethyl, diphenylethyl, etc.

As used herein, “C₅-C₇ monosaccharide” refers to simple sugars of theformula (CH₂O)_(n) wherein n=5-7. The monosaccharides can bestraight-chain or ring systems, and can include a saccharose unit of theformula —CH(OH)—C(═O)—. Examples include erythrose, threose, ribose,arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose,idose, galactose, talose, erythulose, ribulose, xyulose, psicose,fructose, sorbose, tagatose, erythropentulose, threopentulose,glycerotetrulose, glucopyranose, fructofuranose, etc.

As used herein, the term “amino acid” refers to a molecule containingboth an amino group and a carboxyl group. Embodiments of amino acidsinclude α-amino, β-amino, γ-amino acids. The α-amino acids have ageneral formula HOOC—CH(side chain)-NH₂. The amino acids can be in theirD, L or racemic configurations. Amino acids include naturally-occurringand non-naturally occurring moieties. The naturally-occurring aminoacids include the standard 20 α-amino acids found in proteins, such asglycine, serine, tyrosine, proline, histidine, glutamine, etc.Naturally-occurring amino acids can also include non-α-amino acids (suchas (3-alanine, γ-aminobutyric acid, homocysteine, etc.), rare (such as4-hydroxyproline, 5-hydroxylysine, 3-methylhistidine, etc.) andnon-protein (such as citrulline, ornithine, canavanine, etc.) aminoacids. Non-naturally occurring amino acids are well-known in the art,and include analogs of natural amino acids. See Lehninger, A. L.Biochemistry, 2^(nd) ed.; Worth Publishers: New York, 1975; 71-77, thedisclosure of which is incorporated herein by reference. Non-naturallyoccurring amino acids also include α-amino acids wherein the side chainsare replaced with synthetic derivatives. Representative side chains ofnaturally occurring and non-naturally occurring α-amino acids are shownbelow in Table A.

TABLE A CH₃— HS—CH₂— HO—CH₂— HO₂C—CH(NH₂)—CH₂—S—S—CH₂— C₆H₅—CH₂—CH₃—CH₂— HO—C₆H₄—CH₂— CH₃—S—CH₂—CH₂—

CH₃—CH₂—S—CH₂—CH₂— HO—CH₂—CH₂—

CH₃—CH(OH)— HO₂C—CH₂—NHC(═O)—CH₂—

HO₂C—CH₂—CH₂— NH₂C(═O)—CH₂—CH₂—

(CH₃)₂—CH— (CH₃)₂—CH—CH₂— CH₃—CH₂—CH₂—

H₂N—CH₂—CH₂—CH₂— H₂N—C(═NH)—NH—CH₂—CH₂—CH₂— H₂N—C(═O)—NH—CH₂—CH₂—CH₂—

CH₃—CH₂—CH(CH₃)— CH₃—CH₂—CH₂—CH₂— H₂N—CH₂—CH₂—CH₂—CH₂—

As used herein, the term “subject” refers to a warm blooded animal suchas a mammal, preferably a human, or a human child, which is afflictedwith, or has the potential to be afflicted with one or more diseases andconditions described herein.

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention which is effective in reducing,eliminating, treating or controlling the symptoms of theherein-described diseases and conditions. The term “controlling” isintended to refer to all processes wherein there may be a slowing,interrupting, arresting, or stopping of the progression of the diseasesand conditions described herein, but does not necessarily indicate atotal elimination of all disease and condition symptoms, and is intendedto include prophylactic treatment.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. The pharmaceutically acceptable saltsinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,tartaric, citric, glutamic, benzoic, salicylic, toluenesulfonic, oxalic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two. Generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17^(th) ed., Mack Publishing Company, Easton,Pa., 1985, p. 1418, the disclosure of which is hereby incorporated byreference.

As used herein, “prodrug” is intended to include any covalently bondedcarriers which release the active parent drug according to the compoundsof the present invention in vivo when such prodrug is administered to amammalian subject. Since prodrugs are known to enhance numerousdesirable qualities of pharmaceuticals (e.g., solubility,bioavailability, manufacturing, etc.), the compounds of the presentinvention may be delivered in prodrug form. Thus, the present inventioncontemplates prodrugs of the claimed compounds, compositions containingthe same, and methods of delivering the same. Prodrugs of a compound ofthe present invention may be prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Accordingly, prodrugs include, for example, compounds of thepresent invention wherein a hydroxy, amino, or carboxy group is bondedto any group that, when the prodrug is administered to a mammaliansubject, cleaves to form a free hydroxyl, free amino, or carboxylicacid, respectively. Examples include, but are not limited to, acetate,formate and benzoate derivatives of alcohol and amine functional groups;and alkyl, cycloalkyl, aryl, and alkylaryl esters such as methyl, ethyl,cyclopropyl, phenyl, benzyl, and phenethyl esters, etc.

The present invention provides a method of treating diseases andconditions in a subject in need thereof comprising administering to saidsubject a therapeutically effective amount of a compound of formula (I),(I-A), (II), or (II-A). For example, the compounds of formula (I),(I-A), (II), or (II-A) can be used in the treatment of sleepiness,preferably sleepiness associated with narcolepsy, promotion ofwakefulness, treatment of Parkinson's disease, cerebral ischemia,stroke, sleep apneas, eating disorders, preferably eating disordersassociated with a disease, in particular, wherein the disease isanorexia nervosa, stimulation of appetite and weight gain, treatment ofattention deficit hyperactivity disorder, enhancing function indisorders associated with hypofunctionality of the cerebral cortex,including, but not limited to, depression, schizophrenia, fatigue, inparticular, fatigue associated with neurologic disease, such as multiplesclerosis, chronic fatigue syndrome, and improvement of cognitivedysfunction.

The identification of those subjects who are in need of treatment ofherein-described diseases and conditions is well within the ability andknowledge of one skilled in the art. A clinician skilled in the art canreadily identify, by the use of clinical tests, physical examination andmedical/family history, those subjects who are in need of suchtreatment.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the species of subject;its size, age, and general health; the specific disease involved; thedegree of involvement or the severity of the disease; the response ofthe individual subject; the particular compound administered; the modeof administration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

The amount of a compound of formula (I), (I-A), (II), or (II-A) which isrequired to achieve the desired biological effect will vary dependingupon a number of factors, including the dosage of the drug to beadministered, the chemical characteristics (e.g., hydrophobicity) of thecompounds employed, the potency of the compounds, the type of disease,the diseased state of the patient, and the route of administration. Ingeneral terms, the compounds of this invention may be provided in anaqueous physiological buffer solution containing about 0.1 to 10% w/vcompound for parenteral administration. Typical dose ranges are fromabout 1 μg/kg to about 1 g/kg of body weight per day; a preferred doserange is from about 0.01 mg/kg to 100 mg/kg of body weight per day. Apreferred daily dose for adult humans includes about 25, 50, 100 and 200mg, and an equivalent dose in a human child. The preferred dosage ofdrug to be administered is likely to depend on such variables as thetype and extent of progression of the disease or disorder, the overallhealth status of the particular patient, the relative biologicalefficacy of the compound selected, and formulation of the compoundexcipient, and its route of administration.

The compounds of the present invention are capable of being administeredin unit dose forms, wherein the term “unit dose” means a single dosewhich is capable of being administered to a patient, and which can bereadily handled and packaged, remaining as a physically and chemicallystable unit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described hereinafter. Assuch, typical daily dose ranges are from about 0.1 to 100 mg/kg of bodyweight. By way of general guidance, unit doses for humans range fromabout 0.1 mg to about 1000 mg per day. Preferably the unit dose range isfrom about 1 to about 500 mg administered one to four times a day, andeven more preferably from about 10 mg to about 300 mg, two times a day.In an alternate method of describing an effective dose, a preferred oralunit dose is one that is necessary to achieve a blood serum level ofabout 0.05 to 20 μg/ml, and more preferably, of about 1 to about 20μg/ml in a subject.

Compounds provided herein can be formulated into pharmaceuticalcompositions by admixture with one or more pharmaceutically acceptableexcipients. Such compositions may be prepared for use in oraladministration, particularly in the form of tablets or capsules; orparenteral administration, particularly in the form of liquid solutions,suspensions or emulsions; or intranasally, particularly in the form ofpowders, nasal drops, or aerosols; or dermally, for example, topicallyor via trans-dermal patches.

The compositions may conveniently be administered in unit dosage formand may be prepared by any of the methods well known in thepharmaceutical art, for example, as described in Remington: The Scienceand Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.; LippincottWilliams & Wilkins: Philadelphia, Pa., 2000. Pharmaceutically compatiblebinding agents, and/or adjuvant materials can be included as part of thecomposition. Oral compositions will generally include an inert diluentcarrier or an edible carrier.

The tablets, pills, powders, capsules, troches and the like can containone or more of any of the following ingredients, or compounds of asimilar nature: a binder such as microcrystalline cellulose, or gumtragacanth; a diluent such as starch or lactose; a disintegrants such asstarch and cellulose derivatives; a lubricant such as magnesiumstearate; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, or methyl salicylate. Capsules can be in the form of a hardcapsule or soft capsule, which are generally made from gelatin blendsoptionally blended with plasticizers, as well as a starch capsule. Inaddition, dosage unit forms can contain various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar, shellac, or enteric agents. Other oral dosage forms syrup orelixir may contain sweetening agents, preservatives, dyes, colorings,and flavorings. In addition, the active compounds may be incorporatedinto fast dissolve, modified-release or sustained-release preparationsand formulations, and wherein such sustained-release formulations arepreferably bi-modal.

Preferred formulations include pharmaceutical compositions in which acompound of the present invention is formulated for oral or parenteraladministration, or more preferably those in which a compound of thepresent invention is formulated as a tablet. Preferred tablets containlactose, cornstarch, magnesium silicate, croscarmellose sodium,povidone, magnesium stearate, or talc in any combination. It is also anaspect of the present disclosure that a compound of the presentinvention may be incorporated into a food product or a liquid.

Liquid preparations for administration include sterile aqueous ornonaqueous solutions, suspensions, and emulsions. The liquidcompositions may also include binders, buffers, preservatives, chelatingagents, sweetening, flavoring and coloring agents, and the like.Nonaqueous solvents include alcohols, propylene glycol, polyethyleneglycol, vegetable oils such as olive oil, and organic esters such asethyl oleate. Aqueous carriers include mixtures of alcohols and water,buffered media, and saline. In particular, biocompatible, biodegradablelactide polymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers may be useful excipients tocontrol the release of the active compounds. Intravenous vehicles caninclude fluid and nutrient replenishers, electrolyte replenishers, suchas those based on Ringer's dextrose, and the like. Other potentiallyuseful parenteral delivery systems for these active compounds includeethylene-vinyl acetate copolymer particles, osmotic pumps, implantableinfusion systems, and liposomes.

Alternative modes of administration include formulations for inhalation,which include such means as dry powder, aerosol, or drops. They may beaqueous solutions containing, for example, polyoxyethylene-9-laurylether, glycocholate and deoxycholate, or oily solutions foradministration in the form of nasal drops, or as a gel to be appliedintranasally. Formulations for buccal administration include, forexample lozenges or pastilles and may also include a flavored base, suchas sucrose or acacia, and other excipients such as glycocholate.Formulations suitable for rectal administration are preferably presentedas unit-dose suppositories, with a solid based carrier, such as cocoabutter, and may include a salicylate. Formulations for topicalapplication to the skin preferably take the form of an ointment, cream,lotion, paste, gel, spray, aerosol, or oil. Carriers which can be usedinclude petroleum jelly, lanolin, polyethylene glycols, alcohols, ortheir combinations. Formulations suitable for transdermal administrationcan be presented as discrete patches and can be lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive.

The compounds of the current invention can be employed as the soleactive ingredient in a pharmaceutical composition. Alternatively, theycan be used in combination or combined with other pharmaceutical agentsassociated with other disease states. In particular, the compounds offormula (I), (I-A), (II), or (II-A) can be combined with agents that areuseful for the treatment of impaired cognition associated with variousdisease states including, but not limited to, age, trauma, stress ortransient impairment due to chemical imbalance or toxicity, hypersomnia,depression, Alzheimer's Disease, non-Alzheimer's dementias, includingLewy body dementia, vascular dementia and Binswanger's dementia,schizophrenia, and the like. The present invention would encompass,therefore, combinations of the compounds of the current invention witheburnane analogs, heterocyclic inducers of tyrosine hydroxylase,3,4-diphenyl chromans, tacrine metabolites, aza-cyclic compounds,polyamine compounds, or thiamine; nonanticholinergic antidepressantssuch as benzodiazepines; phenothiazines aliphatic such aschlorpromazine; piperidines such as thioridazine; piperazines such astrifluoperazine, fluphenazine and perphenazine; dibenzoxazepines such asloxapine; dihydroindolones such as molindone; thioxanthenes such asthiothixene; butyrophenones such as haloperidol;diphenylbutyl-piperidines such as pimozide; dibenzodiazepine such asclozapine; benzisoxazole such as risperidone; thienobenzodiazepine suchas olanzapine; dibenzothiazepine such as quetiapine; imidazolidinonesuch as sertindole, benzisothiazolyl-piperazine such as ziprasidone, andthe like.

Synthesis

The compounds of the present invention may be prepared in a number ofways well known to those skilled in the art. The compounds can besynthesized, for example, by the methods described below, or variationsthereon as appreciated by the skilled artisan. The appropriatemodifications and substitutions being readily apparent and well known orreadily obtainable from the scientific literature to those skilled inthe art.

It will be appreciated that the compounds of the present invention maycontain one or more asymmetrically substituted carbon atoms, and may beisolated in optically active or racemic forms. Thus, all chiral,diastereomeric, racemic forms and all geometric isomeric forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare and isolate such optically active forms. For example, mixturesof stereoisomers may be separated by standard techniques including, butnot limited to, resolution of racemic forms, normal, reverse-phase, andchiral chromatography, preferential salt formation, recrystallization,and the like, or by chiral synthesis either from chiral startingmaterials or by deliberate synthesis of target chiral centers.

As will be readily understood, functional groups present on thecompounds of the present invention may contain protecting groups duringthe course of synthesis. For example, the amino acid side chainsubstituents of the compounds of formula (I), (I-A), (II), or (II-A) canbe substituted with protecting groups such as benzyloxycarbonyl ort-butoxycarbonyl groups. Protecting groups are known per se as chemicalfunctional groups that can be selectively appended to and removed fromfunctionalities, such as hydroxyl groups and carboxyl groups. Thesegroups are present in a chemical compound to render such functionalityinert to chemical reaction conditions to which the compound is exposed.Any of a variety of protecting groups may be employed with the presentinvention. Preferred protecting groups include the benzyloxycarbonyl(“Cbz”) group, the tert-butyloxycarbonyl (“Boc”) group, and the tosyl(p-toluensulfonyl, “Tos”) group. Other preferred protecting groupsaccording to the invention may be found in Greene, T. W. and Wuts, P. G.M., Protective Groups in Organic Synthesis 2d. Ed., Wiley & Sons, 1991.

Compounds of the present invention may be prepared as outlined in thefollowing schemes. The reagents and starting materials are commerciallyavailable, or readily synthesized by well-known techniques by one ofordinary skill in the arts. All substituents, unless otherwiseindicated, are as previously defined.

A general synthetic procedure is set forth in Scheme A for preparing thecompounds of formula (I) [wherein Y=C(R₁)(R₂) and m, n=0] or (I-A):

Scheme A, Step 1: Synthesis of Compounds of General Structure c:

In step 1a, the appropriate aryl halide a undergoes a metal exchangereaction with an organometallic compound to give the correspondingmetalloaryl compound. For example, an appropriate haloaromatic orhaloheteroaromatic (compound a) is reacted with an appropriate alkyllithium compound in an aprotic solvent at a temperature −78° C. Anappropriate haloaromatic or haloheteroaromatic compound is one where Ar₁is as defined in the final product. An appropriate alkyl lithiumcompound is one that effects a metal-halogen exchange.

In step 1b, an appropriate aryl aldehyde b is added to the previouslyformed metalloaryl compound to give desired di-aryl alcohol c. Forexample, an appropriate aromatic aldehyde or heteroaromatic aldehyde(compound b) in an aprotic solvent is added to reaction product of step1a. An appropriate heteroaromatic aldehyde is one where Ar₂ is asdefined in the final product. Upon completion, the reaction mixture isquenched by an appropriate quenching agent and the product, compound c,is isolated by conventional methods commonly employed by those skilledin the art.

For example, a cooled (−70° C. to −78° C.) solution of an appropriatehaloaromatic or haloheteroaromatic (compound a) in dry ether is reactedwith n-butyllithium (1.1 eqv). After stirring for an additional periodof time to allow the completion of halogen-metal exchange reaction, thenext reactant, an appropriate heteroaromatic aldehyde (compound b) inether is slowly be added to the reaction flask. Stirring is continuedfor an additional 2-3 h at the low temperature. The cooling bath isremoved and the reaction mixture is slowly allowed to come to ambienttemperature, followed by quenching, preferably by a saturated NH₄Clsolution. The mixture is extracted into an organic solvent (ether orethyl acetate). The organic layer is washed with brine, dried (MgSO₄ orNa₂SO₄) and concentrated to give a crude product. Purification isachieved by employing known purification techniques (preferably bycolumn chromatography and/or recrystallization) to provide purecompounds c. The method is an adaptation from a procedure previouslydescribed by Gronowitz, S.; Eriksson, B. Arkiv Kemi 1963, 335,incorporated herein by reference in its entirety. Alternatively, thisclass of compounds wherein Ar₁ is the same as Ar₂ may be generated bytreatment of two equivalents of an appropriate haloheteroaromatic withtwo equivalents of n-butyllithium, followed by one equivalent of ethylformate as described by Nenajdenko, V. G.; Baraznenok, I. L.; Balenkova,E. S. J. Org. Chem. 1998, 6132, incorporated herein by reference in itsentirety.

Scheme A, Step 2: Synthesis of Compounds of General Structure d:

In step 2a, the alcohol moiety of compound c is converted to thecorresponding thiol. The thiol, in step 2b, undergoes a substitutionreaction with an appropriate halogen-substituted alkylcarboxylic acid ofstructure Br-(CH₂)_(m)—Y—(CH₂)_(n), —COOH, to generate compound d. Forexample, di-aryl alcohol c is reacted with thiourea in presence of anacid to convert it to a thiouronium moiety that is subsequentlyhydrolyzed in the presence of an alkaline base and reacted with theappropriate halogen-substituted alkylcarboxylic acid to generatecompound d (step 2b). An appropriate acid derivative is one in which m,n, Y are as defined in the final product.

For example, in step 2a, an appropriate amount of thiourea is taken into48% HBr and water. The mixture is warmed (preferably to 60-70° C.),followed by addition of compound c. The temperature of the reactionmixture is elevated (preferably to 90-95° C.) and the stirring iscontinued for an additional period of time for completion of thereaction. The reaction mixture is cooled to room temperature (in somecases, an ice-bath might be needed) and the precipitated solid should befiltered and thoroughly washed with water.

In step 2b, the wet solid from the previous step is taken intoadditional water and treated with an aqueous base, preferably sodiumhydroxide solution. The mixture is warmed (preferably to 70-80° C., butin some cases a higher temperature might be needed) and to it anappropriate amount of halogen-substituted alkylcarboxylic acidderivative in water (or in some cases, an alcoholic solvent) is added.The reaction mixture is maintained at an elevated temperature(preferably 100-110° C.) for an appropriate period of time, cooled,taken into water and washed with an organic solvent (preferably ether).The basic aqueous layer is acidified with an inorganic acid solution(e.g. aqueous HCl solution). The aqueous (acidic) solution is thenextracted several times into an organic solvent (e.g. ether or ethylacetate). The combined organic layer is washed with brine, dried (MgSO₄or Na₂SO₄) and concentrated to give the crude product that may be useddirectly in the next step. However, purification could be achieved byemploying known purification techniques (e.g. recrystallization) toprovide pure compound d.

The method is an adaptation from a procedure previously described inU.S. Pat. No. 4,177,290, incorporated by reference herein in itsentirety.

Scheme A, Step 3: Synthesis of Compounds of General Structure e:

In step 3a, the carboxylic acid is converted into appropriate acidderivative, which is then reacted with an appropriate amine to givecompound e. For example in step 3a, compound d can be converted to thecorresponding acid chloride, or the corresponding activated ester. Theacid chloride can be obtained by reacting compound d with thionylchloride in an aromatic hydrocarbon solvent in refluxing condition.Alternatively, the activated ester can be obtained by use of variousagents known in the art, such as2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(“TBTU”), N-methylmorpholine (“NMM”) and dimethyl formamide (“DMF”). Instep 3b, the product of step 3a is reacted with an appropriate amine ofstructure NHR₃R₄ to give the desired compound e. An appropriate amine isone which correlates to R₃ and R₄ as defined in the final product.

For example, a solution of an appropriate carboxylic acid (compound d)in either benzene or toluene is brought to reflux temperature and to itis slowly added an appropriate amount of thionyl chloride. The mixtureis refluxed until the disappearance of starting material (as evidencedby analytical techniques), cooled and solvent removed. The resultingresidue is taken into an appropriate organic solvent (preferablytetrahydrofuran or methylene chloride) and treated with ammonia gas (or28% aqueous ammonia hydroxide solution) or an appropriate amine. Thereaction mixture is then partitioned between water and an organicsolvent (preferably ethyl acetate). The separated organic layer iswashed with water, dilute acid, dilute base and brine, dried over adrying agent (e.g. MgSO₄ or Na₂SO₄) and concentrated to give the crudeproduct that may be purified by column chromatography and/orrecrystallization to produce compound e.

Scheme A, Optional Step 4: Synthesis of Compounds of General Structuref:

Compounds of structure e may optionally be oxidized to generatecompounds of structure f. Thus, compound f is prepared by reactingcompound e in an appropriate solvent with an appropriate oxidizingagent. An appropriate oxidizing agent is one that oxidizes the sulfidegroup of compound e. The corresponding product is isolated and purifiedby methods well known in the art.

For example, to a cooled (−15° C. to −25° C.) solution of compound e inan organic solvent (preferably methylene chloride or chloroform), anappropriate oxidizing agent (e.g. m-chloroperoxybenzoic acid [“m-CPBA”],1 equivalent) in the same solvent is slowly added. Stirring is continuedat low temperature until the disappearance of the starting material, asevidenced by various analytical techniques. The reaction mixture is thenthoroughly washed with a saturated sodium bicarbonate solution, waterand brine, respectively, dried over a drying agent (e.g. MgSO₄ orNa₂SO₄) and concentrated. The desired product (compound f) is purified,if needed, by employing known purification techniques (preferably bycolumn chromatography and/or recrystallization). In some cases, theoxidation is performed by employing 50% H₂O₂ in glacial acetic acidsolvent.

A general synthetic procedure is set forth in Scheme B for preparing thecompounds of formula (II) [wherein ring A is phenylene; Y=C(R₁)(R₂) andm, n=0] and (II-A):

Scheme B, Steps 1, 2, and 3: Synthesis of Compounds of General Structuredd, ee and ff.

The synthetic steps in Scheme B involve the same multistep generalmethod described in Scheme A, wherein Scheme B, steps 1-3 corresponds toScheme A, steps 2-4, respectively.

A general synthetic procedure is set forth in Scheme C for preparing thecompounds of formula (I-A), wherein n=0 and Y is

Scheme C, Steps 1 and 2: Synthesis of Compounds of General Structure dddand eee.

The synthetic steps in Scheme C, steps 1 and 2 involve the samemultistep general method described in Scheme A, steps 2-3, respectivelyto give compounds of structure eee.

Scheme C, Step 3: Synthesis of Compounds of General Structure fff.

The amide moiety in compound eee is converted to corresponding thioamidemoiety fff with an appropriate sulfur-transfer reagent. For example, amixture of compound eee and Lawesson's reagent (1.05 eqv) in a suitablesolvent (dimethoxyethane or tetrahydrofuran) is heated to reflux untilthe disappearance of the starting material. After cooling, the desiredproduct (compound fff) is obtained by employing known purificationtechniques (preferably by column chromatography and/orrecrystallization).

Scheme C, Step 4: Synthesis of Compounds of General Structure ggg.

The thioamide moiety in compound fff is cyclized to the correspondingthiazole moiety. For example, a mixture of compound fff and anappropriate bromomethyl ketone (1.1 eqv) in a suitable solvent (e.g.ethanol) is heated to reflux until the disappearance of the startingmaterial. After cooling, the desired product (compound ggg) is obtainedby employing known purification techniques (preferably by columnchromatography and/or recrystallization).

Scheme C, Steps 5-6: Synthesis of Compounds of General Structure hhh andiii.

The synthetic steps in Scheme C, steps 5 and 6 involve the samemultistep general method described in Scheme A, steps 3 and 4,respectively to give compounds of structure hhh and iii.

A general synthetic procedure is set forth in Scheme D for preparing thecompounds of formula (II-A), wherein n=0 and Y is

Scheme D, Steps 1-6: Synthesis of Compounds of General Structure hhhhand iiii.

The synthetic steps in Scheme D involve the same multistep generalmethod described in Scheme C to give compounds of structure hhhh andoptionally, iiii.

A synthetic procedure is set forth in Reaction Scheme E for preparingcompounds of formula (I) or (I-A) wherein R₁ or R₂ can be taken togetherwith either R₃ or R₄ to form a 3-7 member heterocyclic ring. Thesubsequently formed ring is represented in Scheme E by “G”. In thepresent scheme, R₁ is taken together with R₃ to form heterocyclic ring“G”. It is understood that R₁ may be also be taken with R₄ to form ring“G”, or R₂ may be also be taken with R₃ to form ring “G”, or R₂ may bealso be taken with R₄ to form ring “G”. The reagents and startingmaterials are commercially available, or readily synthesized bywell-known techniques by one of ordinary skill in the arts. In ReactionScheme E, all substituents, unless otherwise indicated, are aspreviously defined.

Scheme E, Steps 1 and 2: Synthesis of Compounds of General Structure 60,Containing Compounds of Formula (I) Wherein Either R₁ or R₂ are takentogether with either R₃ or R₄ to Form a 3-7 Member Heterocyclic Ring“G”.

In the first step, an appropriate mercaptolactam 59 is reacted with anappropriate diarylmethanol, compound 27, in the presence of a weak acid,in order to affect nucleophilic displacement at the methanol carbon toform the corresponding thioether. The appropriate mercaptolactam 59 andappropriate diaryl- or diheteroarylmethanol, 27 are ones in which Ar₁,Ar₂, R₂ and R₄ are as defined in the final product.

In the second step, the thioether formed in the first step is optionallyoxidized with an appropriate oxidizing agent to provide compound 60. Anappropriate oxidizing agent is one that oxidizes the thioether to itscorresponding sulfoxide or sulfone.

A synthetic procedure is set forth in Reaction Scheme F for preparingcompounds of formula (II-A), wherein R₁ or R₂ can be taken together witheither R₃ or R₄ to form a 3-7 member heterocyclic ring. A similarprocedure may be utilized to prepare the corresponding compounds offormula (II-A). The subsequently formed ring is represented in Scheme Eby “G”. In the present scheme, R₁ is taken together with R₃ to formheterocyclic ring “G”. It is understood that R₁ may be also be takenwith R₄ to form ring “G”, or R₂ may be also be taken with R₃ to formring “G”, or R₂ may be also be taken with R₄ to form ring “0”. Thereagents and starting materials are commercially available, or readilysynthesized by well-known techniques by one of ordinary skill in thearts. In Reaction Scheme F, all substituents, unless otherwiseindicated, are as previously defined.

Scheme F, steps 1 and 2: Synthesis of Compounds of General Structure 62,Containing Compounds of Formula (II-A) Wherein Either R₁ or R₂ are takentogether with Either R₃ or R₄ to Form a 3-7 Member Heterocyclic Ring“G”.

In the first step, an appropriate mercaptolactam 59 is reacted with anappropriate diaryl- or diheteroarylmethanol, 27a, in the presence of aweak acid, in order to affect nucleophilic displacement at the methanolcarbon to form the corresponding thioether. The appropriatemercaptolactam 61 and appropriate diaryl- or diheteroarylmethanol, 27aare ones in which A, X, R₂ and R₄ are as defined in the final product.

In the second step, the thioether formed in the first step is optionallyoxidized with an appropriate oxidizing agent to provide compound 62. Anappropriate oxidizing agent is one that oxidizes the thioether to itscorresponding sulfoxide or sulfone.

EXAMPLES

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments. These examples aregiven for illustration of the invention and are not intended to belimiting thereof. The following Examples 1-6 were synthesized accordingto Scheme 1.

Preparation of Compound C:

To a vigorously stirred mixture of thiourea (compound B, 5 g, 0.066mol), 48% HBr (30 mL) and water (5 mL) at 70-75° C. was added9-hydroxyfluorene (compound A, 9.28 g, 0.051 mol) in small portions,followed by additional amount of water (30 mL). The reaction mixture wasthen heated to 100-105° C. (bath temperature), maintained there foranother 30 min and cooled to room temperature. The precipitated solidwas filtered, washed with water and ether, successively and dried undervacuum to generate 14 g of the corresponding thiouronium salt that wasused in the next step without any further purification.

To a vigorously stirred mixture of the above-mentioned thiouronium salt(10.47 g,) in 10 N NaOH (10.26 mL) and water (25 mL) at 60-65° C. wasslowly added 3-bromopropionic acid (5.24 g, 0.034 mol) in water (20 mL).The reaction mixture was then heated to 105-110° C. (bath temperature),maintained there for another 30 min, cooled to room temperature, dilutedwith water (25 mL), and washed with ether (3×50 mL). The basic aqueouslayer was acidified (pH 23) with conc. HCl and extracted into ethylacetate (3×100 mL). The combined organic layer was dried (MgSO₄) andconcentrated to generate 7.80 g of compound C that was used in the nextstep without any further purification; ¹H-NMR (CDCl₃) δ 7.80 (m, 4H),7.30 (m, 4H), 4.90 (s, 1H), 2.10 (m, 4H).

Preparation of Compound D:

This compound was prepared from compound A, following the same procedureas described above for the synthesis of compound D, except that4-bromobutyric acid was used in place of 3-bromopropionic acid in thealkylation step; ¹H-NMR (CDCl₃) δ 7.70 (m, 4H), 7.40 (m, 4H), 4.80 (s,1H), 2.20 (t, 2H), 2.00 (t, 2H), 1.40 (m, 2H).

Preparation of Compound E:

To a refluxing solution of compound C (7.8 g, 0.029 mol) in benzene (40mL) was slowly added thionyl chloride (5.3 mL). The mixture was refluxedfor another 2 h, cooled, filtered and concentrated under reducedpressure to generate 8 g of compound E that was immediately taken intonext step without any further purification.

Preparation of Compound F:

This compound was prepared from compound D, following the same procedureas described above for the synthesis of compound E from compound C.

Example 1 Synthesis of Compound G

Compound E (8 g) from previous step was dissolved in methylene chloride(20 mL) and added to a vigorously stirred, cooled (0° C.) 28% NH₄OHsolution (50 mL). The ice-bath was removed and stirring was continuedfor another hour. The reaction mixture was diluted with water (30 mL)and extracted into methylene chloride (2×30 mL). The combined organiclayer was washed with water (2×20 mL), 3% NaHCO₃ solution (2×30 mL),brine (1×30 mL), dried (Na₂SO₄) and concentrated to give a residue thatwas triturated with ether to generate 6.30 g of compound G; ¹H-NMR(DMSO-d₆) δ 7.90 (d, 2H), 7.70 (d, 2H), 7.40 (m, 4H), 7.30 (broad, 1H),6.80 (broad, 1H), 5.20 (s, 1H), 2.30 (t, 2H), 2.10 (t, 2H).

Example 2 Synthesis of Compound H

This compound was prepared from compound E, following the same procedureas described above for the synthesis of compound G, except thatdimethylamine was used in place of 28% NH₄OH in the amination step;¹H-NMR (DMSO-d₆) δ 7.90 (d, 2H), 7.60 (d, 2H), 7.40 (m, 4H), 5.20 (s,1H), 2.70 (2 singlets, 6H), 2.20 (m, 4H).

Example 3 Synthesis of Compound I

This compound was prepared from compound F, following the same procedureas described above for the synthesis of compound G from compound E;¹H-NMR (DMSO-d₆) δ 7.80 (d, 2H), 7.60 (d, 2H), 7.40 (m, 4H), 7.10(broad, 1H), 6.70 (broad, 1H), 5.10 (s, 1H), 2.10 (t, 2H), 2.00 (t, 2H),1.50 (m, 2H).

Example 4 Synthesis of Compound II-1

To a solution of compound G (5.15 g, 0.019 mol) in glacial acetic acid(20 mL) at room temperature was slowly added 50% H₂O₂ (1.2 eqv). Themixture was stirred for 1 h, poured into ice-water and filtered. Theprecipitated solid was thoroughly washed with water, followed by etherand dried under high vacuum to generate 4.42 g of compound II-1; whitesolid; mp 163-164° C.; R_(t) 7.57 min. ¹H-NMR (DMSO-d₆) δ 8.10-7.50 (aseries of m, 8H), 7.40 (broad, 111), 6.90 (broad, 1H), 5.70 (s, 1H),2.30 (m, 4H).

Example 5 Synthesis of Compound II-2

This compound was prepared from compound H, following the same procedureas described above for the synthesis of compound II-1 from compound G;white solid; mp 110-112° C.; R_(t) 8.64 min. ¹H-NMR (DMSO-d₆) δ 8.00 (t,2H), 7.70 (d, 1H), 7.60 (d, 1H), 7.50 (m, 2H), 7.40 (q, 2H), 5.60 (s,1H), 2.80 (s, 3H), 2.70 (s, 3H), 2.60-2.20 (a series of m, 4H).

Example 6 Synthesis of Compound II-3

This compound was prepared from compound I, following the same procedureas described above for the synthesis of compound II-1 from compound G;white solid; mp 161-162° C.; R_(t) 7.61 min. ¹H-NMR (DMSO-d₆) δ8.20-7.60 (a series of m, 8H), 7.40 (broad, 1H), 6.90 (broad, 1H), 5.80(s, 1H), 2.30 (m, 4H), 1.80 (m, 2H).

The following Examples 7-8 were synthesized according to Scheme 2.

Example 7 Synthesis of Compound J

To a stirred solution of compound C (1.9 g, 0.007 mol) in dry DMF (20mL) at 0° C. was added N-methylmorpholine (“NMM”)(1.92 mL), followed by2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(“TBTU”)(3.38 g. 0.0105 mol). The mixture was stirred for 10 min and toit added (L)-alaninamide (as hydrochloride salt) (1.3 g, 0.0105 mol) indry DMF (5 mL). The cooling bath was removed and the mixture was stirredfor another 2 h. It was then poured into cold water (25 mL) andextracted into ethyl acetate (3×50 mL). The combined organic layer waswashed with water, 2% citric acid, 3% sodium bicarbonate, water andbrine, successively. Drying (MgSO₄) and solvent evaporation produced aresidue that on trituration with cold ether generated 1.93 g of compoundJ; ¹H-NMR (DMSO-d₆) δ 770 (m, 3H), 7.50 (d, 2H), 7.20 (m, 4H), 7.10(broad, 1H), 6.80 (broad, 1H), 5.00 (s, 1H), 4.00 (m, 1H), 2.10 (m, 2H),2.00 (m, 2H), 0.90 (d, 3H).

Example 8 Synthesis of Compound II-4

This compound was prepared from compound J, following the same procedureas described above for the synthesis of compound II-1 from compound G(Scheme 1); white solid (diastereomeric mixture); R_(t) 7.16 min. ¹H-NMR(DMSO-d₆) δ 8.30 (2 overlapping d, 1H), 8.20-7.60 (a series of m, 8H),7.50 (d, 1H), 7.10 (d, 1H), 5.80 (s, 1H), 4.20 (m 1H), 2.60-2.40 (2 setsof m, 4H), 1.30 (2 overlapping d, 3H).

The following Examples 9-18 were synthesized according to Scheme 3.

Preparation of Compound 33:

Scheme 3, Step 1:

In step 1a, 3-bromothiophene (10.22 g)(compound 31) in dry ether at atemperature −70° C. to −78° C. was reacted with n-butyllithium (25 ml of2.5 M, 1.1 equivalents). After stirring for an additional period of timeto allow for the completion of the halogen-metal exchange reaction,3-thiophenecarboxaldehyde (6.39 g)(compound 32) in ether was slowlyadded to the reaction flask. Stirring was continued for an additional2-3 h at the low temperature. The cooling bath was removed and thereaction mixture was slowly allowed to come to ambient temperature,followed by quenching, preferably by 50% aqueous NH₄Cl solution. Themixture was extracted into an organic solvent (ether or ethyl acetate).The organic layer was washed with brine, dried (MgSO₄ or Na₂SO₄) andconcentrated to give a crude product. Purification may be achieved byemploying known purification techniques (preferably by columnchromatography and/or recrystallization) to provide pure compound 33;¹H-NMR (CDCl₃) δ 7.40 (d, 2H), 7.30 (s, 2H), 7.10 (d, 2H), 6.00 (d, 1H),2.20 (d, 2H). The method was an adaptation from a procedure previouslydescribed by Gronowitz, S.; Eriksson, B. Arkiv Kemi 1963, 335,incorporated herein by reference in its entirety.

Preparation of Compound 34:

Scheme 3, Step 2:

In the first step, thiourea (5 g, 1.3 equivalents) was taken into 48%HBr and water. The mixture was warmed (preferably to 60°-70° C.),followed by addition of compound 33 (10 g). The temperature of thereaction mixture was elevated (preferably to 90°-95° C.) and stirringwas continued for an additional period of time for completion of thereaction. The reaction mixture was then cooled to room temperature (insome cases, an ice-bath might be needed) and the precipitated solid wasfiltered and thoroughly washed with water.

The wet solid was then taken into additional water and treated with anaqueous base, preferably sodium hydroxide solution. The mixture waswarmed (preferably to 70°-80° C., but in some cases, a highertemperature might be needed) and to it chloroacetic acid (4.8 g, 1.1equivalents) in water was added. The reaction mixture was maintained atan elevated temperature (preferably 100°-110° C.) for an appropriateperiod of time, cooled, taken into water and washed with an organicsolvent (preferably ether). The basic aqueous layer was acidified withan inorganic acid solution (e.g. aqueous HCl solution). The aqueous(acidic) solution was then extracted several times into an organicsolvent (e.g. ether or ethyl acetate). The combined organic layer waswashed with brine, dried (MgSO₄ or Na₂SO₄) and concentrated to give thecrude product 34 that may be used directly in the next step. However,purification may also be achieved by employing known purificationtechniques (e.g. recrystallization) to provide pure compound 34; ¹H-NMR(CDCl₃) δ 7.30 (d, 2H), 7.20 (s, 2H), 7.10 (d, 2H), 5.40 (s, 1H), 3.10(s, 2H).

The method is an adaptation from a procedure previously described inU.S. Pat. No. 4,177,290 (issued on Dec. 4, 1979) that is incorporated byreference herein in its entirety.

Preparation of Compound 35:

Scheme 3, Step 3:

A solution of the thioacid 34 (9.0 g) in benzene was brought to refluxtemperature and to it was slowly added 1.1 equivalents of thionylchloride. The mixture was refluxed until the disappearance of thestarting material (as evidenced by analytical techniques), cooled andthe solvent removed to give the crude product 35 that may be useddirectly in the next step. However, purification may also be achieved byemploying known purification techniques (e.g. recrystallization) toprovide pure compound 35.

Example 9 Synthesis of Compound 36

Scheme 3, Step 4:

The resulting thioacid chloride 35 (9.5 g) from the previous step wastaken into an appropriate organic solvent (preferably tetrahydrofuran ormethylene chloride) and treated with ammonia gas (or 28% aqueoussolution). The reaction mixture is then partitioned between water andethyl acetate. The separated organic layer is washed with water, diluteacid, and brine, dried over a drying agent (e.g. MgSO₄ or Na₂SO₄) andconcentrated to produce 6.40 g of compound 36. Analytical Data: whitesolid; mp 88.5-89.5° C.; R_(t) 9.61 min. ¹H-NMR (CDCl₃) δ 7.40 (d, 2H),7.30 (s, 2H), 7.20 (d, 2H), 6.40 (broad, 1H), 5.50 (broad, 1H), 5.40 (s,1H), 3.10 (s, 2H).

Example 10 Synthesis of Compound 37

In a procedure similar to that of Example 9, treatment of 2.15 g offreshly prepared compound 35 with 2.2 g of n-propylamine generated acrude material that was purified by flash column chromatography (eluent:30% ethyl acetate in hexanes) to generate 1.71 g of compound 37.Analytical Data: viscous oil, R_(t) 12.30 min. ¹H-NMR (DMSO-d₆) δ 7.90(t, 1H), 7.50 (d, 2H), 7.40 (s, 2H), 7.10 (d, 2H), 5.60 (s, 1H), 3.30(d, 1H), 3.10 (m, 3H), 1.30 (m, 2H), 0.80 (t, 3H).

Example 11 Synthesis of Compound 38

In a procedure similar to that of Example 9, treatment of 2.56 g offreshly prepared compound 35 with dimethylamine gas generated a crudematerial that was purified by flash column chromatography (eluent: 30%ethyl acetate in hexanes) to produce 1.96 g of compound 38. AnalyticalData: white solid; mp 71-72° C.; R_(t) 11.08 min. ¹H-NMR (CDCl₃) δ7.30-7.10 (m, 6H), 5.50 (s, 1H), 3.20 (s, 2H), 3.00 and 2.90 (2 sets ofs, 6H).

Example 12 Synthesis of Compound 39

In a procedure similar to that of Example 9, treatment of 2.15 g offreshly prepared compound 35 with 2.74 g of diethylamine generated acrude product that was purified by flash column chromatography (eluent:25% ethyl acetate in hexanes) to generate 1.56 g of compound 39.Analytical Data: white solid; mp 83-84° C.; R_(t) 13.37 min. ¹H-NMR(CDCl₃) δ 7.30-7.10 (m, 6H), 5.60 (s, 1H), 3.40 (q, 2H), 3.30 (q, 2H),3.20 (s, 2H), 1.10 (2 overlapping t, 6H).

Example 13 Synthesis of Compound 40

In a procedure similar to that of Example 9, treatment of 2.15 g offreshly prepared compound 35 with 4 g of morpholine generated a crudeproduct that was purified by flash column chromatography (eluent: 50%ethyl acetate in hexanes) to generate 2.02 g of compound 40. AnalyticalData: white solid; mp 75.5-78° C.; R_(t) 11.21 min. ¹H-NMR (CDCl₃) δ7.40-7.20 (2 sets of m, 6H), 5.50 (s, 1H), 3.70 (m, 4H), 3.60 (m, 2H),3.40 (m, 2H), 3.20 (s, 2H).

Example 14 Synthesis of Compound I-9

To a cooled (−15° C. to −25° C.) solution of compound 36 (5.50 g) ineither methylene chloride or chloroform, 1 equivalent of the oxidizingagent m-chloroperoxybenzoic acid (m-CPBA) in the same solvent was slowlyadded. Stirring was continued at the low temperature until thedisappearance of the starting material, as evidenced by variousanalytical techniques. The reaction mixture was then thoroughly washedwith a saturated sodium bicarbonate solution, water and brine,respectively, dried over a drying agent (e.g. MgSO₄ or Na₂SO₄) andconcentrated. The resulting material was then purified by columnchromatography and/or recrystallization to give compound I-9 (5.50 g).Analytical Data: white solid, mp 131-130° C. ¹H-NMR (CDCl₃) δ 7.40 (m,4H), 7.25 (d, 1H), 7.15 (d, 1H), 6.90 (broad, 1H), 5.60 (broad, 1H),5.45 (s, 1H), 3.45 (d, 1H), 3.10 (d, 1H).

Example 15 Synthesis of Compound I-10

In a procedure similar to that of Example 14, compound 37 (1.67 g) wasoxidized with 1 equivalent of the oxidizing agent m-chloroperoxybenzoicacid (m-CPBA), and then purified to give compound I-10 (1.40 g).Analytical Data: semi-solid; R_(t) 8.95 min. ¹H-NMR (DMSO-d₆) δ 8.00 (t,1H), 7.40 (m, 4H), 7.10 (m, 2H), 5.30 (s, 1H), 3.20 (d, 1H), 3.10 (m,1H), 3.00 (d, 1H), 2.90 (m, 1H), 1.20 (m, 2H), 0.80 (t, 3H).

Example 16 Synthesis of Compound I-11

In a procedure similar to that of Example 14, compound 38 (1.91 g) wasoxidized with 1 equivalent of the oxidizing agent m-chloroperoxybenzoicacid (m-CPBA), and then purified to give compound I-11 (1.63 g).Analytical Data: white solid; mp 93-96° C; R_(t) 7.79 min. ¹H-NMR(CDCl₃) δ 7.50-7.30 (m, 6H), 5.70 (s, 1H), 3.60 (d, 1H), 3.40 (d, 1H),3.10 and 2.90 (2 sets of s, 6H).

Example 17 Synthesis of Compound I-12

In a procedure similar to that of Example 14, compound 39 (1.53 g) wasoxidized with 1 equivalent of the oxidizing agent m-chloroperoxybenzoicacid (m-CPBA), and then purified to give compound I-12 (1.35 g).Analytical Data: white solid; mp 93-95° C; R_(t) 9.70 min. ¹H-NMR(CDCl₃) δ 7.40-7.20 (m, 6H), 5.70 (s, 1H), 3.60 (d, 1H), 3.40 (m, 2H),3.30 (d, 1H), 3.20 (m, 2H), 1.20 (t, 3H), 1.10 (t, 3H).

Example 18 Synthesis of Compound I-13

In a procedure similar to that of Example 14, compound 40 (2.00 g) wasoxidized with 1 equivalent of the oxidizing agent m-chloroperoxybenzoicacid (m-CPBA), and then purified to give compound I-13 (1.60 g).Analytical Data: white solid; mp 59-73° C; R_(t) 8.03 min. ¹H-NMR(CDCl₃) δ 7.40-7.20 (2 sets of m, 6H), 5.60 (s, 1H), 3.80-3.20 (a seriesof m, 10H).

Example 19 Synthesis of Compound I-22

Compound I-22 was prepared following the same multistep general methodas described in Scheme A, utilizing 3-bromothiophene and benzaldehye instep 1. (M+H)=280.

Examples 20-39 Synthesis of Compounds I-1 Through 1-7 and 1-26 Through1-38

Compounds I-1 through 1-7 and 1-26 through 1-38 were prepared followingthe same multistep general method as described in Scheme A utilizing theappropriately substituted amine NHR₃R₄ in step 3b. The analytical datais represented by each compound's mass spectrum (M+H) as shown in thefollowing Table 3.

TABLE 3 Example Compound (M + H) 20 I-1  300 21 I-2  328 22 I-3  328 23I-4  371 24 I-5  328 25 I-6  362 26 I-7  356 27 I-26 330 28 I-27 397 29I-28 399 30 I-29 322 (M + Na) 31 I-30 377 32 I-31 377 33 I-32 377 34I-33 384 35 I-34 340 36 I-35 355 37 I-36 294 38 I-37 376 39 I-38 348

The following Examples 40-41 were synthesized according to Scheme 4.

Preparation of Compound 43:

A mixture of compound 41 (0.75 g)(Dondoni, A. et. al. J. Org. Chem.1988, pp. 1748-1761), acetic anhydride (3 equivalents) and anhydrouspyridine (2-3 ml/mmol of alcohol) was stirred overnight at roomtemperature, or until the reaction was complete by thin layerchromatography. The reaction mixture was then poured into cold water andextracted into ethyl acetate (3×25 mL). The combined organic phase wassuccessively washed with saturated sodium bicarbonate solution, water,brine, dried (sodium sulfate) and concentrated to generate the desiredproduct compound 43 (0.84 g). Analytical Data: R_(f)=0.6 (2.5%methanol/ethyl acetate); ¹H-NMR (CDCl₃) δ 7.72 (s, 1H), 7.47 (m, 1H),7.38-7.22 (m, 5H), 7.11 (s, 1H), 2.17 (s, 3H).

Preparation of Compound 44:

Compound 42 (0.92 g) was reacted in a manner similar to that describedabove in the preparation of compound 41. The resulting crude ester waspurified by flash chromatography (eluent: 4:1 hexane/ethyl acetate) togive 0.41 g of compound 44. Analytical Data: R_(f)=0.32 (4:1hexane/ethyl acetate); ¹H-NMR (CDCl₃) δ 7.83 (s, 1H), 7.42 (s, 1H), 7.36(m, 1H), 7.17 (m, 1H), 7.00 (m, 1H), 2.19 (s, 3H).

Preparation of Compound 45:

To a stirring solution of compound 43 (0.84 g) and methyl thioglycolate(1.2 equivalents) in anhydrous dichloromethane (4-5 mL/mmol) at 0° C.under argon was added trimethylsilyl trifluoromethane (TMS-triflate, 1equivalent). The reaction mixture was allowed to warm to roomtemperature and stirred until complete (2-6 h). It was then diluted withdichloromethane, washed with saturated sodium bicarbonate solution,dried (sodium sulfate), concentrated and dried under high vacuum to givecompound 45 (1.01 g) that was used directly in the next step without anyfurther purification. Analytical Data: R_(f)=0.62 (2.5% methanol/ethylacetate); ¹H-NMR (CDCl₃) δ 7.75 (s, 1H), 7.5 (d, 1H), 7.38-7.27 (m, 5H),5.72 (s, 1H), 3.69 (s, 3H), 3.25 (q, 2H).

Preparation of Compound 46:

Compound 44 (0.41 g) was reacted in a manner similar to that describedabove in the preparation of compound 45 to give compound 46 (0.30 g).Analytical Data: R_(f)=0.62 (2.5% methanol/ethyl acetate); ¹H NMR(CDCl₃) δ 7.75 (s, 1H), 7.39 (s, 1H), 7.36 (m, 1H), 7.17 (broad, 1H),6.94 (m, 1H), 6.07 (s, 1H), 3.72 (s, 3H), 3.30 (q, 2H).

Preparation of Compound 47:

Anhydrous ammonia was bubbled into a stirring solution of compound 45(1.0 g) in methanol (10 mL/mmol) at 0° C. for 5-10 minutes. The reactionmixture was allowed to warm to room temperature, stirred for additional5-7 h, concentrated under reduced pressure and dried under vacuum. Thecrude product was purified by flash chromatography (eluent: 5%methanol/ethyl acetate) to give 0.48 g of compound 47. Analytical Data:R_(f)=0.20 (5% methanol/ethyl acetate); ¹H-NMR (CDCl₃) δ 7.77 (s, 1H),7.47 (d, 1H), 7.44-7.27 (m, 5H), 5.53 (broad, 1H), 3.22 (q, 2H).

Preparation of Compound 48:

Compound 46 (0.30 g) was reacted in a manner similar to that describedabove in the preparation of compound 47 to give compound 48 (0.25 g).Analytical Data: R_(f)=0.20 (5% methanol/ethyl acetate); ¹H-NMR (CDCl₃):δ 7.72, (s, 1H), 7.31 (s, 1H), 7.28 (m, 1H), 7.17 (s, 1H), 6.97 (m, 1H),6.84 (broad, 1H), 6.11 (broad, 1H), 5.86 (s, 1H), 3.25 (q, 2H).

Example 40 Synthesis of Compound I-39

To a stirring solution of compound 47 (0.48) in anhydrousdichloromethane (10 mL/mmol) at −78° C. was added a solution of m-CPBA(1.0 equivalent) in dichloromethane (5-8 mL/mmol). After an additionalstirring for 1 h, the reaction mixture was allowed to warm to −30 to−40° C. and quenched with 10% aqueous Na₂S₂O₃ solution. Separatedorganic phase was successively washed with saturated sodium bicarbonatesolution, water and brine, dried (sodium sulfate), and concentrated togenerate compound I-37 (0.31 g). Analytical Data: R_(f)=0.13 (5%methanol/ethyl acetate); ¹H-NMR (CDCl₃) major diastereomer: δ 7.92 (s,1H), 7.61 (m, 2H), 7.44-7.36 (m, 5H), 7.00 (broad, 1H), 5.61 (s, 1H),3.42 (q, 2H); minor diastereomer: δ 7.86 (s, 1H), 7.55 (m, 2H),7.44-7.36 (m, 5H), 6.83 (broad, 1H), 5.55 (s, 1H), 3.61 (q, 2H).

Example 41 Synthesis of Compound I-40

Compound 48 (0.25 g) was reacted in a manner similar to that describedabove in the preparation of compound 47 to give compound I-39 (0.105 g)(diastereomeric mixture). Analytical Data: ¹H-NMR (DMSO-d₆) majordiastereomer: δ 8.03 (s, 1H), 7.92 (s, 1H), 7.78 (broad, 1H), 7.68 (s,1H), 7.36 (broad, 1H)), 7.17 (m, 1H), 6.50 (s, 1H), 3.47 (q, 2H); minordiastereomer: δ 7.97 (s, 1H), 7.86 (s, 1H), 7.78 (broad, 1H), 7,72 (s,1H), 7.36 (broad, 1H), 7.22 (m, 1H), 6.39 (s, 1H), 3.36 (q, 2H).

Example 42 Synthesis of Compound II-9

Starting with 9-hydroxyfluorene, this compound was prepared followingthe same multistep general method as described in Scheme 3 above, andutilizing L-Alanine-NH₂ in the amination step. Analytical Data: whitesolid (diastereomeric mixture); R_(t) 7.27 min and 7.41 min. ¹H-NMR(DMSO-d₆) δ 8.40-7.00 (a series of m and d, 11H), 5.60 and 5.70 (2 setsof s, 1H), 4.20 (m, 1H), 3.20 and 3.00 (2 sets of dd, 2H), 1.20 (2overlapping doublets, 3H).

Example 43 Synthesis of Compound II-23

Starting with 9-hydroxyfluorene, this compound was prepared followingthe same multistep general method as described in Scheme 3 above, andutilizing 28% aqueous ammonia in the amination step. Analytical Data:white solid; mp 178.5-180° C.; R_(t) 7.48 min. ¹H-NMR (CDCl₃) δ7.90-7.40 (a series of m, 8H), 6.60 (broad, 1H), 5.40 (s, 1H), 5.30(broad, 1H), 2.80 (d, 1H), 2.60 (d, 1H).

Example 44 Synthesis of Compound II-25

Starting with dibenzosuberol, this compound was prepared following thesame multistep general method as described in Scheme 3 above, andutilizing 28% aqueous ammonia in the amination step. Analytical Data:white solid; mp 182-190° C.; R_(t) 8.43 min. ¹H-NMR (DMSO-d₆) δ 7.80 (d,1H), 7.60 (d, 1H), 7.40 (m, 8H), 5.50 (s, 1H), 3.60 (m, 2H), 3.50 (d,1H), 3.40 (d, 1H), 2.90 (m, 2H).

Example 45 Synthesis of Compound II-26

Starting with dibenzosuberol, this compound was prepared following thesame multistep general method as described in Scheme 3 above, utilizingdimethylamine in the amination step. Analytical Data: white solid; mp112.5-115° C.; R_(t) 10.36 min. ¹H-NMR (DMSO-d₆) δ 7.60 (d, 1H), 7.40(m, 7H), 5.50 (s, 1H), 4.00 (d, 1H), 3.60 (d, 1H), 3.50 (m, 2H), 2.90(s, 3H), 2.80 (m, 2H), 2.70 (s, 3H).

Examples 46-91 Synthesis of Compounds II-6 Through II-8, II-10 ThroughII-15, II-24, II-27, II-30 Through II-54, II-56 Through II-91

Compounds II-6 through II-8, II-10 through II-15, II-24, II-27, II-30through II-54, II-56 through II-91 were prepared following the samemultistep general method as described in Scheme B incorporating theappropriate reactants to form the desired product. The analytical datais represented by each compound's mass spectrum (M+H) as shown in thefollowing Table 4.

TABLE 4 Example Compound (M + H) 46 II-6  314 47 II-7  342 48 II-8  30049 II-10 348 50 II-11 314 51 II-12 348 52 II-13 314 53 II-14 328 54II-15 341 55 II-24 371 56 II-27 288 57 II-30 286 58 II-31 415 59 II-32363 60 II-33 363 61 II-34 316 62 II-35 300 63 II-36 326 64 II-37 298 65II-38 376 66 II-39 288 67 II-40 329 68 II-41 343 69 II-42 318 70 II-43328 71 II-44 343 72 II-45 376 73 II-46 330 74 II-47 358 75 II-48 343 76II-49 343 77 II-50 371 78 II-51 359 79 II-52 373 80 II-53 369 81 II-54286 82 II-56 316 83 II-57 359 84 II-58 314 85 II-59 328 86 II-60 334 87II-61 340 88 II-62 385 89 II-63 384 90 II-64 338 91 II-65 384

The following Example 92 was synthesized according to Scheme 5.

Preparation of Compound M:

A mixture of dimethyl phthalate (compound K, 10 g, 0.51 mol),3,4-dimethoxyacetophenone (compound L, 9.74 g, 0.054 mol), and powderedsodium methoxide (2.76 g, 0.051 mol) was heated at reflux overnight,cooled to room temperature, and concentrated in vacuo. The yellow slurrywas suspended in water (100 mL), stirred for 10 min, acidified with 6NHCl (pH 1-2), and filtered. The residue was placed in ethanol (200 mL),heated to reflux for 30 min, cooled to room temperature, and filtered.The residue was washed with cold ethanol and dried in vacuo to generatecompound M as a bright yellow fluffy solid (4.1 g) that was used withoutany further purification. Analytical Data: ¹H-NMR (CDCl₃) δ 3.99 (s,3H), 4.02 (s, 3H), 6.99 (d, 1H), 7.68-7.75 (m, 2H), 7.85 (m, 2H), 8.07(d, 1H), 8.09 (s, 1H); MS: (M+H)⁺=311.

Preparation of Compound N:

A mixture of compound M (3.37 g, 0.011 mol), hydrazine (0.41 mL, 0.013mol) and ethanol (250 mL) under nitrogen was heated to reflux for 6 h,cooled to room temperature and filtered. The residue was washed withethanol and dried to give compound N as a yellow solid (2.0 g).Analytical Data: ¹H NMR (CDCl₃) δ 3.85 (s, 3H), 3.89 (s, 3H), 7.17 (d,1H), 7.38-7.43 (m, 1H), 7.55 (m, 2H), 7.60 (d, 1H), 7.85 (d, 1H), 7.95(s, 1H); MS: (M+H)⁺=307.

Preparation of Compound O:

To a stirred solution of compound N (0.084 g, 0.27 mmol) in THF/H₂O(3:1, 8 mL) at room temperature under nitrogen was added solid sodiumborohydride (0.029 g, 0.63 mmol) in one portion. The reaction mixturewas cooled to 0° C., stirred for 1 h, warmed to room temperature,diluted with ethyl acetate and washed with water. The organic phase wasdried (magnesium sulfate) and concentrated in vacuo. The residue, ontrituration with ether, generated compound O (0.077 g) as a yellow solidthat was used without further purification. Analytical Data: ¹H NMR(CDCl₃) δ 3.86 (s, 3H), 3.87 (s, 3H), 5.53 (s, 1H), 6.79 (d, 1H), 7.29(t, 2H), 7.46 (d, 1H), 7.50 (s, 2H), 7.58 (t, 1H); MS: (M+H)⁺=309.

Preparation of Compound P:

To a stirred solution of compound 0 (1.55 g, 0.005 mol) in CH₂Cl₂ (40mL) under nitrogen at 0° C. was added methyl thioglycolate (0.54 mL,0.006 mmol). Next, trifluoroacetic anhydride (1.42 mL, 0.01 mol) wasadded dropwise to the reaction mixture. The reaction mixture was stirredat 0° C. for 0.5 h, warmed to room temperature, stirred overnight,quenched with saturated aqueous sodium bicarbonate and extracted intoethyl acetate (3×25 mL). The organic layer was washed with water, brine,dried (magnesium sulfate), and concentrated in vacuo to generatecompound P as a yellow solid (1.75 g) that was used without any furtherpurification. Analytical Data: ¹H NMR (CDCl₃) δ 2.77 (q, 2H), 3.33 (s,3H), 3.93 (s, 3H), 4.00 3H), 4.99 (s, 1H), 6.96 (d, 1H), 7.23-7.42 (m,2H), 7.47 (d, 1H), 7.49 (d, 1H), 7.64 (d, 1H), 7.69 (d, 1H), 7.72 (d,1H); MS: (M+H)⁺=397.

Example 92 Synthesis of Compound II-66

Starting from compound P, this compound was generated following theprocedure as described above for the preparation of compound 47, and inExample 35 for the synthesis of compound I-37. Thus, 0.050 mg ofcompound P, on treatment with ammonia in the first step, followed byoxidation with m-CPBA in the next step, generated 0.011 g of compoundII-66. Analytical Data: ¹H-NMR (CDCl₃) δ 2.75 (d, 1H), 2.88 (d, 1H),3.92 (s, 3H), 3.96 (s, 3H), 5.67 (s, 1H), 6.80 (s, 1H), 6.94 (d, 1H),7.37 (t, 1H), 7.45-7.52 (m, 2H), 7.58 (d, 1H), 7.64 (s, 1H), 7.79 (d,1H); MS: (M+H)⁺=420.

Compounds of formula (VI) and (VII) (Tables 2A and 2B) are readilyprepared using the appropriate cyclic maleimides. For example, thecyclic maleimides used in the preparation compounds VI-1, 2, 6, 7, 8(Table 2A) and VIII-1, 2, 6, 8 (Table 2B) are commercially available.Other cyclic maleimides are known in the literature (see, for example,Bayer et al. Montash. Chem. 1997, 91 and Kakiuchi et al. Chem. Lett.1998, 1001, both of which are incorporated by reference herein in theirentirety).

In addition, a general synthetic scheme is set forth in Scheme 6 forpreparation of cyclic imides (C3 and C4) utilized in the synthesis ofcompounds VI-3, 5 (Table 2A) and VIII-3, 4 (Table 2B).

In Scheme 6, the reaction of maleic anhydride (compound G1) with anappropriate amine (compound H1, wherein R is —(CH₂)₂OMe or(s)-CH(Me)CH₂OH) generates the corresponding maleimic acid (compoundM1). Cyclization of compound M1 in presence of Ac₂O/NaOAc at roomtemperature or in toluene/triethylamine under reflux conditionsgenerates compounds C3 and C4.

Preparation of Compound C3:

To a solution of maleic anhydride (compound G1, 1 equiv.) in acetic acidwas added 2-methoxyethylamine (compound H1, R=(CH₂)₂OMe, 1 equiv.) in adropwise fashion. After stirring overnight at room temperature, thereaction mixture was concentrated to generate crude compound M1 that wastaken in a mixture of acetic anhydride and NaOAc (0.6 equiv.). Theresulting mixture was stirred at 90° C. for 2 h, cooled to roomtemperature, quenched with cold water and extracted into ether. Thecombined organic layers were washed with brine, dried (magnesiumsulfate) and concentrated to generate compound C3, which was directlyused without further purification; ¹H-NMR (DMSO-d₆): δ 7.02 (s, 2H),3.54 (m, 2H), 3.44 (m, 2H), 3.20 (s, 3H).

Preparation of Compound C4:

A solution of (S)-2-aminopropanol (compound H1, R=(s)-CH(Me)CH₂OH, 1equiv.) in absolute ethanol was slowly added to a solution of maleicanhydride (compound G1, 1 equiv.). The resulting mixture was stirred atroom temperature overnight. The separated solid was filtered, washedwith ether, taken into toluene and treated with triethylamine. Theresulting mixture was refluxed for 4 h under a Dean-Stark trap, cooledto room temperature, concentrated and passed through a pad of silica gel(eluent: ethyl acetate) to give compound C4; ¹H-NMR (Acetone-d₆): δ 6.80(s, 2H), 4.20 (m, 1H), 3.91 (m, 2H), 3.64 (m, 1H), 1.29 (d, 3H).

The following Examples 92a-92q were synthesized following the proceduresoutlined in Scheme 7.

In Scheme 7, the reaction of an appropriate thiol (generated fromcorresponding thiouronium salt), with an appropriate cyclic imide inpresence of a base generates the corresponding thioether. The thioethermay be oxidized to give the corresponding sulfoxide. For example, thiolB1, generated from its corresponding thiouronium salt A1 (prepared fromcompound A as disclosed in Scheme 1), reacts with N-methylmaleimide(compound C2) in presence of triethylamine to generate thioether D2 thaton subsequent oxidation with hydrogen peroxide in glacial acetic acidproduces the corresponding sulfoxide, compound VIII-2 (Table 2B).Alternatively, the thioether may be directly produced by reacting theappropriate thiouranium salt with the appropriate cyclic imide in thepresence of a base. Thus, thioether D1 was directly produced from thereaction of its corresponding thiouranium salt A1 with maleimide (C1),in presence of 10 N NaOH. Oxidation of D1 generated the correspondingsulfoxide VIII-1 (Table 2B).

Example 92a Synthesis of Compound VIII-1

A mixture of compound A1 (4 g, 12.46 mmol.), 10 N NaOH (4 mL) and water(10 mL) was stirred at 70° C. for 0.5 h. Maleimide (compound C1, 1.2 g,12.37 mmol.) in ethanol (20 mL) was then added to the reaction mixtureand stirring was continued at 70° C. for another 2 h. After cooling toroom temperature, the separated solid was filtered, washed successivelywith water, hexane and ether. The filtrate containing the desiredproduct was extracted into ethyl acetate. The combined organic layerswere washed successively with water and brine, dried (MgSO₄), andconcentrated to furnish the crude product that was purified by flashchromatography (hexane:ethyl acetate 1:1) to give 0.510 g of compoundD1; ¹H-NMR (DMSO-d₆): δ 11.33 (s, 1H), 7.90-7.32 (a series of m, 8H),5.49 (s, 1H), 3.79 (dd, 1H), 2.64 (dd, 1H), 2.24 (dd, 1H).

Oxidation of compound D1 with hydrogen peroxide, as described above,generated the title compound as a mixture of diastereomers; R_(t)=10.16min; ¹H-NMR (DMSO-d₆): δ 11.82 (s, 0.11H), 11.44 (s, 0.89H), 8.03-7.39(a series of m, 8H), 5.99 (s, 0.1H), 5.72 (s, 0.89H), 4.58 (m, 0.11H),3.22 (dd, 0.891H), 2.79 (dd, 3.32, 0.11H), 2.55 (dd, 0.89H), 1.67 (dd,0.89H). MS: 312 (M+H), 334 (M+Na).

Example 92b Synthesis of Compound VIII-2

A mixture of compound A1 (1 equiv) in water and 10 N NaOH (4-5 equiv)was stirred at 70° C. for 3-5 h. The mixture was cooled to 0° C.,acidified with dil HCl and extracted into ether. The combined organiclayers were washed with brine, dried (magnesium sulfate), andconcentrated to furnish compound B1 that was used without furtherpurification; ¹H-NMR (DMSO-d₆): δ 7.87-7.35 (a series of m, 8H), 5.21(d, 1H), 3.55 (d, 1H).

A mixture of compound B1 (1 equiv.), compound C2 (1 equiv.), andtriethylamine in ethyl acetate:methanol (4:1) was stirred at roomtemperature for 2-5 h, concentrated and purified by flash chromatography(hexane:ethyl acetate 2:1) to give compound D2; ¹H-NMR (DMSO-d₆): δ7.90-7.35 (series of m, 8H), 5.49 (s, 1H), 3.76 (m, 1H), 2.73 (s, 3H),2.61(dd, 1H), 2.24 (dd, 1H).

Oxidation of compound D2 with hydrogen peroxide, as described above,generated the title compound as a mixture of diastereomers; R_(t) 10.30min; ¹H-NMR (DMSO-d,): δ 8.04-7.37 (a series of m, 8H), 5.98 (s, 0.08H),5.77 (s, 0.92H), 4.61 (m, 0.08H), 3.31-2.50 (a series of m and dd,5.0811), 1.58 (dd, 0.92H). MS: 348 (M+Na).

Example 92c Synthesis of Compound VI-1

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)9.20 min. and 9.41 min (diastereomers); ¹H-NMR (DMSO-d₆): δ 11.62 and11.53 (2 singlets, 1H), 7.57-7.32 (a series of m, 1011), 6.07 (s, 0.4H),5.33 (s, 0.6H), 3.74 (m, 0.6H), 3.55 (m, 0.4H), 3.14 (dd, 0.4H), 2.96(dd, 0.6H), 2.82 (dd, 0.4H), 2.57 (dd, 0.6H). MS: 312 (M−H).

Example 92d Synthesis of Compound VI-2

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)8.05 min. and 8.17 min (diastereomers). ¹H-NMR (DMSO-d₆): δ 7.58-7.26 (aseries of m, 10H), 6.04 (s, 1H), 3.31-2.49 (a series of m, 6H). MS: 350(M+Na).

Example 92e Synthesis of Compound VI-3

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)8.38 min and 8.46 min (diastereomers); ¹H-NMR (DMSO-d₆): δ 7.58-7.01 (aseries of m, 10H), 6.03 (s, 0.23H), 5.38 (s, 0.77H), 3.84-3.01 (a seriesof m, 9.23H), 2.61 (dd, 0.77H). MS: 394 (M+Na).

Example 92f Synthesis of Compound VI-4

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)7.38 min. (overlapping diastereomers); ¹H-NMR (DMSO-d₆): δ 7.58-7.33 (aseries of m, 10H), 6.02 (s, 0.33H), 5.38 (s, 0.67H), 4.67 (m, 1H),3.79-2.94 (a series of m, 5.33H), 2.60 (dd, 0.67H). MS: 380 (M+Na).

Example 92g Synthesis of Compound VI-5.

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)7.98 min, 8.16 min, and 10.42 min (diastereomers); ¹H-NMR (DMSO-d₆): δ7.58-7.35 (a series of m, 8H), 6.03 and 6.02 (two overlapping s, 0.46H),5.36 (s, 0.54H), 4.70 (m, 0.54H), 4.14-2.50 (series of m, 6H), 1.22-1.12(overlapping d, 3H). MS: 372(M+H), 394 (M+Na).

Example 92h Synthesis of Compound VI-6

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data:R_(t)7.78 min and 7.88 min (diastereomers); ¹H-NMR (DMSO-d₆): δ7.63-7.22 (two m, 8H), 6.06 (s, 0.66H), 5.47 (s, 0.3411), 3.82 (m,0.34H), 3.69(m, 0.66H), 3.14(dd, 0.66H), 2.95(m, 1H), 2.84 and 2.81 (twos, 3H), 2.9 (dd, 0.34H). MS: 386 (M+Na).

Example 92i Synthesis of Compound VI-7

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)8.48 min and 8.70 min (diastereomers); ¹H-NMR (DMSO-d₆): δ 11.52 (br,1H), 7.69-7.60 (m, 4H), 7.29 (m, 2H), 6.32 (s, 0.11H), 5.60 (s, 0.9H),3.75 (m, 1H), 3.81 (dd, 1H), 2.66-2.32 (m, 1H). MS: 348 (M+Na).

Example 92j Synthesis of Compound VI-8

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)8.70 min (overlapping diastereomers). ¹H-NMR (DMSO-d₆): δ 11.62 and11.53 (two br, 1H), 7.74-7.25 (m, 8H), 6.18 and 6.13 (two s, 0.4H), 5.47and 5.45 (two singlets, 0.6H), 3.78-2.49 (a series of m, 3H). MS: 342(M+Na).

Example 92k Synthesis of Compound VIII-3

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)10.79 min. and 10.98 min (diastereomers). ¹H-NMR (DMSO-d₆): δ 8.04-7.37(a series of m, 8H), 5.97 (s, 0.5H), 5.75 (s, 0.5H), 4.65 (m, 0.5H),3.69-2.55 (a series of m, 2.081), 1.65 (dd, 0.5H). MS: 392 (M+Na).

Example 92l Synthesis of Compound VIII-4

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)9.18 min and 9.30 min (diastereomers); ¹H-NMR (DMSO-d₆): δ 8.05-7.37 (aseries of m, 8H), 5.96 (s, 0.09H), 5.77 (s, 0.91H), 4.80 and 4.48 (twom, 1H), 3.57-2.49 (a series of m, 5.09H), 1.51 (dd, 0.91H). MS: 378(M+H), 403 (M+Na).

Example 92m Synthesis of Compound VIII-5

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)10.03 min, 10.30 min, 10.42 min and 11.11 min (diastereomers). ¹H-NMR(DMSO-d₆): δ 8.05-7.37 (a series of m, 8H), 5.95 and 5.94 (twooverlapping singlets, 0.36H), 5.76 (s, 0.64H), 4.85-2.49 (a series of m,6H), 1.29 and 1.08 (two sets of overlapping d, 3H). MS: 370 (M+H), 392(M+Na).

Example 92n Synthesis of Compound VIII-6

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)7.22 min (overlapping diastereomers); ¹H-NMR (DMSO-d₆): δ 11.23 and10.89 (two singlets, 1H), 8.04-7.38 (a series of m, 8H), 6.00 (s,0.37H), 5.77 (s, 0.63H), 4.65 (m, 0.37H), 3.32 (m, 0.63H), 3.22 (dd,0.37H), 2.86 (dd, 0.37H), 2.59 (dd, 0.63H), 1.76 (dd, 0.6311). MS: 328(M+H), 350 (M+Na).

Example 92o Synthesis of Compound VIII-7

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)13.90 min and 14.12 min (diastereomers); ¹H-NMR (DMSO-d₆): δ 8.04-6.80(a series of m, 12H), 5.98 (s, 0.111H), 5.76 (s, 0.89H), 4.65 (d,0.22H), 4.37 (s, 1.78H), 3.69 (s, 3H), 3.31 (m, 1H), 2.93 (m, 0.111H),2.63 (dd, 0.89H), 1.78 (dd, 1H). MS: 554 (M+Na).

Example 92p Synthesis of Compound VIII-8

The title compound was prepared using the appropriate starting materialsand following the methodologies described above. Analytical data: R_(t)9.48 min and 9.62 min (diastereomers); ¹H-NMR (DMSO-d₆): δ 8.04-7.09 (aseries of m, 13H), 5.97 (s, 0.1H), 5.84 (s, 0.9H), 4.70 (m, 0.11H),3.38-3.24 (m, 1H), 3.04 (m, 0.11H), 2.72 (dd, 0.9H), 1.63 (dd, 0.9H).MS: 388 (M+H), 410 (M+Na).

Example 92q Synthesis of Compound VII-1

The title compound was prepared from compound A1(Scheme 7) following thesimilar procedure as described for the synthesis of compound VIII-1 withthe exception of utilizing 3-bromo-1-phenyl-pyrrolidin-2-one in place ofmaleimide in the first step. Analytical data: R_(t) 9.36 min and 9.72min (mixture of diastereomers); ¹H-NMR (DMSO-d₆): δ 8.03-7.12 (a seriesof m, 13H), 6.19 (s, 0.11H), 5.66 (s, 0.9H), 3.71-3.28 (three m, 3H),2.32 (m, 1H), 1.30 (m, 1H). MS: 374 (M+H), 396 (M+Na).

The following Examples 92r-92s were synthesized according to Scheme 8.

In Scheme 8, the reaction of an appropriate thiol (compound U) with3-bromo-glutarimide (T), in presence of a base, generated correspondingcompound W. Oxidation of appropriate compound W produced compounds VI-9and VIII-9, respectively. 3-Bromoglutarimide was prepared fromprocedures described in Japanese Patent Application No. 8308, 1961 andJapanese Patent Application No. 5277, 1960, both of which areincorporated by reference herein in their entirety.

Example 92r Synthesis of Compound VI-9

To a cooled (0° C.) solution of diphenylmethylthiol (1 equiv.) and3-bromo-glutarimide (1 equiv.) in dry tetrahydrofuran, DBU(1,8-Diazabicyclo[5.4.0]undec-7-ene)(1.05 equiv.) was added dropwise.The cooling bath was removed and the mixture was stirred at roomtemperature for 1-2 h, diluted with hexane:ethyl acetate (1:1) andwashed successively with water and brine. Drying (magnesium sulfate) andsolvent evaporation gave a crude product that was triturated with ethylacetate to generate intermediate compound W (where R=Ph₂CH); ¹H-NMR(DMSO-d₆): δ 10.81(s, 1H), 7.53-7.22 (a series of m, 10H), 5.52 (s, 1H),3.3-1.81 (a series of m, 5H).

Oxidation of above-prepared compound W with hydrogen peroxide, followingpreviously disclosed methodology, generated the title compound as amixture of diastereomers; R_(t) 9.20 min and 9.44 min; ¹H-NMR (DMSO-d₆):δ 11.17 & 11.12 (two singlets, 1H), 7.57-7.33 (a series of m, 10H), 5.75(s, 0.35H), 5.43 (s, 0.65H), 3.45-2.53 (a series of m, 5H). MS: 350(M+Na).

Example 92s Synthesis of Compound VIII-9

Following the same procedures as described above for the synthesis ofVI-9, the title compound, starting from 9-fluorenylthiol, was alsoprepared as a diastereomeric mixture; R_(t)7.18 min and 7.47 min; ¹H-NMR(DMSO-d,): 11.32 and 11.16 (two singlets, 1H), 7.99-7.35 (a series of m,8H), 5.79 and 5.66 (two singlets, 1H), 4.26 and 4.07 (two multiplets,1H), 2.70-2.10 (a series of m, 4H). MS: 326 (M+H), 348 (M+Na).

Example 93 Demonstration of Wake-Promoting Activity of Compound I-9

The methodology utilized is as described by Edgar and Seidel, Journal ofPharmacology and Experimental Therapeutics, 283:757-769, 1997,incorporated herein in its entirety by reference.

Animal Surgery.

Adult, male Wistar rats (275-320 g from Charles River Laboratories,Wilmington, Mass.) were anesthetized (Nembutal, 60 mg/kg, ip) andsurgically prepared with implants for recording of chronic EEG and EMGrecording. The EEG implants consisted of stainless steel screws (2frontal (+3.9 AP from bregma, ±2.0 ML) and 3 occipital (−6.4 AP, ±5.5ML). Two Teflon-coated stainless steel wires were positioned under thenuchal trapezoid muscles for EMG recording. All leads were soldered to aminiature connector (Microtech, Boothwyn, Pa.) and gas sterilized withethylene oxide before surgery. The implant assembly was affixed to theskull by the combined adhesion of the EEG recording screws,cyanoacrylate applied between the hermetically sealed implant connectorand skull and dental acrylic. An antibiotic (Gentamycin) wasadministered for 3 to 5 days postsurgery. At least 3 weeks were allowedfor postsurgical recovery.

Recording Environment.

Rats were housed individually within specially modified Nalgenemicroisolator cages equipped with a low-torque slip-ring commutator(Biella Engineering, Irvine, Calif.) and a custom polycarbonatefilter-top riser. These cages were isolated in separate, ventilatedcompartments of a stainless steel sleep-wake recording chamber. Food andwater were available ad libitum and ambient temperature was 24±1° C. A24-h light-dark cycle (light/dark 12-12-) was maintained throughout thestudy by 4-watt fluorescent bulbs located approximately 5 cm from thetop of each cage. Light intensity was 30 to 35 lux at midlevel insidethe cage. Animals were undisturbed for 3 days both before and after thetreatments.

Automated Data Collection.

Sleep and wake stages were determined with SCORE, a microcomputer-basedsleep-wake and physiological monitoring system. SCORE™design features,validation in rodents and utility in preclinical drug evaluation havebeen reported elsewhere (Van Gelder, et al., 1991; Edgar, et al., 1991,1997; Seidel, et al, 1995, incorporated by reference herein in theirentirety). In the present study, the system monitored amplified (X10,000) EEG (bandpass, 1-30 Hz; digitization rate, 100 Hz) andintegrated EMG (bandpass, 10-100 Hz, root mean square integration).Arousal states were classified on-line as NREM sleep, REM sleep, wake ortheta-dominated wake every 10s by use of EEG period and amplitudefeature extraction and ranked membership, algorithms. Individuallytaught EEG-arousal-state templates and EMG criteria differentiated REMsleep from theta-dominated wakefulness (Welsh, et al., 1985,incorporated by reference herein in its entirety). Data quality wasassured by frequent on-line inspection of the EEG and EMG signals. Rawdata quality and sleep-wake scoring was scrutinized further by acombination of graphical and statistical assessments of the data as wellas visual examination of the raw EEG wave forms and distribution ofintegrated EMG values.

Drug Administration and Study Design.

Compound I-9 was suspended in sterile 0.25% methylcellulose (pH=6.2;Upjohn Co., Kalamazoo, Mich.) or methylcellulose vehicle alone wasinjected intraperitoneally in a volume of 1 ml/kg. Sample size (n) was13 animals per treatment group.

EEG Spectral Analysis.

Each 10-s epoch of raw EEG signal was digitized (100 Hz) for 24 h andwakefulness was scored as described previously by Edgar and Seidel(1996), incorporated by reference herein in its entirety.

Data Analysis and Statistics.

The principal variable recorded was minutes per hour of wake. Treatmentgroups were compared post-treatment by repeated-measures ANOVA. In thepresence of a significant main effect, Dunnett's contracts (a=0.05)assessed differences between active treatment groups and vehiclecontrols, unless otherwise specified.

Results.

FIG. 1 illustrates degree of wakefulness in rats treated at time zerowith either 100 mg/kg, ip of compound I-9 (solid line) ormethylcellulose vehicle (stippled line). Compound I-9 producedwakefulness beyond that observed in vehicle-treated animals that lasteduntil approximately 110 minutes following administration.

Example 94 Demonstration of Wake-Promoting Activity of Compound II-23

The methodology utilized is based on that described by Edgar and Seidel,Journal of Pharmacology and Experimental Therapeutics, 283:757-769,1997, and incorporated herein in its entirety by reference.

Animal Surgery.

Adult, male Wistar rats (275-320 g from Charles River Laboratories,Wilmington, Mass.) were anesthetized (Nembutal, 45 mg/kg, ip) andsurgically prepared with implants for recording of chronic EEG and EMGrecording. The EEG implants were made from commercially availablecomponents (Plastics One, Roanoke, Va.). EEG's were recorded fromstainless steel screw electrodes (2 frontal (+3.0 mm AP from bregma,±2.0 mm ML) and 2 occipital (−4.0 mm AP, ±2.0 mm ML)). Two Teflon-coatedstainless steel wires were positioned under the nuchal trapezoid musclesfor EMG recording. All electrode leads were inserted into a connectorpedestal and the pedestal, screws, and wires affixed to the skull byapplication dental acrylic. Antibiotic was administered post surgicallyand antibiotic cream was applied to the wound edges to preventinfection. At least 1 week elapsed between surgery and recording.Animals are tested for approximately 6-8 weeks and then sacrificed.

Recording Environment.

Postsurgically, rats were housed individually in an isolated room. Atleast 24 hrs. prior to recording, they were placed in Nalgene containers(31×31×31 cm) with a wire-mesh top, and entry to the room was prohibiteduntil after recording had ended except for dosing. The containers wereplaced on a 2-shelf rack, 4 per shelf. Food and water were available adlibitum, ambient temperature was 21° C., and humidity was 55%.White-noise was provided in the background (68 db inside the containers)to mask ambient sounds. Fluorescent overhead room lights were set to a24 hr. light/dark cycle (on at 7 AM, off at 7 PM). Light levels insidethe containers were 38 and 25 lux for the top and bottom shelvesrespectively.

Data Acquisition.

EEG and EMG signals were led via cables to a commutator (Plastics One)and then to pre-amplifiers (model 1700, A-M Systems, Carlsborg, Wash.).EEG and EMG signals were amplified (10K and 1K respectively) andbandpass filtered between 0.3 and 500 Hz for EEG, and between 10 and 500Hz for EMG. These signals were digitized at 128 samples per second usingICELUS sleep research software (M. Opp, U. Texas; see Opp, Physiologyand Behavior 63:67-74, 1998, and Imeri, Mancia, and Opp, Neuroscience92:745-749, 1999, incorporated by reference herein in their entirety)running under Labview 5.1 software and data acquisition hardware(PCI-MIO-16E-4; National Instruments, Austin, Tex.). On the day ofdosing, data was recorded from 11 AM to 6 PM.

Sleep/Wake Scoring.

Sleep and wake stages were determined manually using ICELUS software.This program displays the EEG and EMG data in blocks of 6 sec. alongwith the EEG-FFT. Arousal state was scored as awake (WAK), rapideye-movement (REM), or slow-wave or non-REM sleep (NREM) according tovisual analysis of EEG frequency and amplitude characteristics and EMGactivity (Opp and Krueger, American Journal of Physiology 266:R₆₈₈-95,1994; Van Gelder, et al., 1991; Edgar, et al., 1991, 1997; Seidel, etal, 1995, incorporated by reference herein in their entirety).Essentially, waking activity consists of relative low-amplitude EEGactivity with relatively lower power in the lower frequency bands from0.5-6 Hz, accompanied by moderate to high level EMG activity. In aparticular waking state (“theta-waking”), EEG power can be relativelyfocused in the 6-9 Hz (theta) range, but significant EMG activity isalways present. NREM sleep is characterized by relative high-amplitudeEEG activity with relatively greater power in the low frequency bandsfrom 0.5-6 Hz, accompanied by little or no EMG activity. REM sleep ischaracterized by moderate and constant amplitude EEG focused in thetheta (6-9 Hz range), similar to waking theta, but with no EMG activity.

Drug Administration and Study Design.

Compounds were evaluated on groups of 4 or 8 rats which were tested in 2sessions at least 2 days apart. Initial studies used a crossover design,such that rats received either vehicle or test compound during eachsession. Animals were pseudo-randomized so that they did not receive thesame drug twice. Compound II-23 was suspended in sterile 0.25%methylcellulose (pH=6.2; Upjohn Co., Kalamazoo, Mich.) at 30 mg/ml. Thisstudy was carried out on 8 rats which were tested in 2 sessions 5 daysapart (overall, 7 rats received compound II-23 and 6 methylcellulosevehicle). Dosing was carried out at noon, while the rats werepredominantly asleep. Each rat was lifted out of its container, given anintraperitoneal. injection in a volume of 3.33 ml/kg, and replaced.Dosing required approximately 8 minutes.

Data Analysis and Statistics.

The principal outcome measure was minutes per hour of wakefulness. Theprimary outcome measure for purposes of determining activity in theseexperiments consists of the total integrated wake time for the first 3hours post dosing relative to vehicle control. Thus, vehicle treatedanimals typically average 20% wake time during the recording period, ora total of 0.2*180=36 min. A 2-tailed, unpaired t-test (Statview 5.0,SAS Institute, Inc., Cary, N.C.) was performed on the wake time valuesfor drug and vehicle treated animals, and compounds with p<0.05 weredeemed significantly wake-promoting. Waking activity was also evaluatedfor successive half-hour periods beginning with the time of dosing, andindividual t-tests performed at each time point to establish theduration of significant wake-promoting activity.

Results.

FIG. 2 illustrates degree of wakefulness in rats treated at noon witheither 100 mg/kg, ip. of compound II-23 (solid triangles) ormethylcellulose vehicle (open circles). Each point represents the meanpercent of time awake for the succeeding half hour. The dosing procedureproduced a transient (˜20 min.) period of elevated wakefulness in bothtreatment groups compared to pre-dosing baseline activity. CompoundII-23 produced significantly greater wakefulness than that observed invehicle-treated animals (p<0.05).

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated in their entirety herein by reference:

Touret, et al., Neuroscience Letters, 189:43-46, 1995.

Van Gelder, R. N. et al., Sleep 14:48-55, 1991.

Edgar, D. M., J. Pharmacol. Exp.Ther. 282:420-429, 1997.

Edgar and Seidel, J. Pharmacol. Exp. Ther., 283:757-69, 1997.

Hernant et al., Psychopharmacology, 103:28-32, 1991.

Lin et al., Brain Research, 591:319-326, 1992.

Opp and Krueger, American Journal of Physiology 266:R₆₈₈-95, 1994

Panckeri et al., Sleep, 19(8):626-631, 1996.

Seidel, W. F., et al., J. Pharmacol. Exp. Ther. 275:263-273, 1995.

Shelton et al., Sleep 18(10):817-826, 1995.

Welsh, D. K., et al., Physiol. Behav. 35:533-538, 1985.

Although the present invention has been described in considerabledetail, those skilled in the art will appreciate that numerous changesand modifications may be made to the embodiments and preferredembodiments of the invention and that such changes and modifications maybe made without departing from the spirit of the invention. It istherefore intended that the appended claims cover all equivalentvariations as fall within the scope of the invention.

What is claimed is:
 1. A compound of the formula (II-A):

wherein X is a bond, —CH₂CH₂—, —O—, —S(O)_(y)—, —N(R₈)—, —CHN(R₈)—,—CH═CH—, —CH₂—CH═CH—, C(═O), —C(R₈)═N—, —N═C(R₈)—, —C(═O)—N(R₈)—, or—NR₈—C(═O)—; Rings A and B, together with the carbon atoms to which theyare attached, are each independently selected from: (a) a 6-memberedaromatic carbocyclic ring in which from 1 to 3 carbon atoms may bereplaced by hetero atoms selected from oxygen, nitrogen and sulfur; andb) a 5-membered aromatic carbocyclic ring in which either: i) one carbonatom is replaced with an oxygen, nitrogen, or sulfur atom; ii) twocarbon atoms are replaced with a sulfur and a nitrogen atom, an oxygenand a nitrogen atom, or two nitrogen atoms; or iii) three carbon atomsare replaced with three nitrogen atoms, one oxygen and two nitrogenatoms, or one sulfur and two nitrogen atoms; wherein Ring A and Ring Bmay each be independently substituted with 1-3 substituents selectedfrom: a) H, C₆-C₁₀ aryl, heteroaryl, F, Cl, Br, I, —CN, —CF₃, —NO₂, —OH,—OR₇, —O(CH₂)_(p)NR₉R₁₀, —OC(═O)R₇, —OC(═O)NR₉R₁₀, —O(CH₂)_(p)OR₈,—CH₂OR₈, —NR₉R₁₀, —NR₈S(═O)₂R₇, —NR₈C(═O)R₇, or —NR₈C(═S)R₇; b)—CH₂OR₁₁; c) —NR₈C(═O)NR₉R₁₀, —NR₈C(═S)NR₉R₁₀, —CO₂R₁₂, —C(═O)R₁₃,—C(═O)NR₉R₁₀, —C(═S)NR₉R₁₀, —CH═NOR₁₂, —CH═NR₇, —(CH₂)_(p)NR₉R₁₀,—(CH₂)_(p)NHR₁₁, —CH═NNR₁₂R₁₂A, —C(═NR₈)NR_(8A)R_(8B)—NR₈C(═NH)R_(8A),—NR₈C(═NH)NR_(8A)R_(8B),

d) —S(O)_(y)R₇, —(CH₂)_(p)S(O)_(y)R₇, —CH₂S(O)_(y)R₇; and e) C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, where: 1) each alkyl, alkenyl,or alkynyl group is unsubstituted; or 2) each alkyl, alkenyl or alkynylgroup is independently substituted with 1 to 3 groups independentlyselected from C₆-C₁₀ aryl, heteroaryl, F, Cl, Br, I, CF₃, —CN, —NO₂,—OH, —OR₇, —CH₂OR₈, —NR₉R₁₀, —O—(CH₂)_(p)—OH, —S—(CH₂)_(p)—OH,—X₁(CH₂)_(p)OR₇, X₁(CH₂)_(p)NR₉R₁₀, —X₁(CH₂)_(p)C(═O)NR₉R₁₀,—X₁(CH₂)_(p)C(═S)NR₉R₁₀, —X₁(CH₂)_(p)OC(═O)NR₉R₁₀, —X₁(CH₂)_(p)CO₂R₈,—X₁(CH₂)_(p)S(O)_(y)R₇, —X₁(CH₂)_(p)NR₈C(═O)NR₉R₁₀, —C(═O)R₁₃, —CO₂R₁₂,—OC(═O)R₇, —C(═O)NR₉R₁₀, —OC(═O)NR₁₂R_(12A), O-tetrahydropyranyl,—C(═S)NR₉R₁₀, —CH═NNR₁₂R_(12A), —CH═NOR₁₂, —CH═N₇, —CH═NNHCH(N═NH)NH₂,—NR₈CO₂R₇, —NR₈C(═O)NR₉R₁₀, —NR₈C(═S)NR₉R₁₀, —NHC(═NH)NH₂, —NR₈C(═O)R₇,—NR₈C(═S)R₇, —NR₈S(═O)₂R₇, —S(O)_(y)R₇, —S(═O)₂NR₁₂R_(12A),—P(═O)(OR₈)₂, —OR₁₁, and a C₅-C₇ monosaccharide where each hydroxylgroup of the monosaccharide is independently either unsubstituted or isreplaced by H, C₁-C₄ alkyl, C₁-C₄ alkoxy, or —O—C(═O)R₇; R₃ and R₄ arethe same or different and are each selected from H, C₁-C₆ alkyl, —OH,—CH(R₆)—CONR_(8A)R_(8B), provided that R₃ and R₄ are not both OH, or R₃and R₄, together with the nitrogen to which they are attached, form a3-7 member heterocyclic ring; R₆ is H, C₁-C₄ alkyl or the side chain ofan α-amino acid; R₇ is C₁-C₆ alkyl, C₆-C₁₀ aryl, or heteroaryl; R₈,R_(8A) and R_(8B) are each independently H, C₁-C₄ alkyl, or C₆-C₁₀ aryl;R₉ and R₁₀ are independently selected from H, C₁-C₄ alkyl, and C₆-C₁₀aryl; or R₉ and R₁₀ together with the nitrogen to which they areattached, form a 3-7 member heterocyclic ring; R₁₁ is the residue of anamino acid after the hydroxyl group of the carboxyl group is removed;R₁₂ and R_(12A) are each independently selected from H, C₁-C₆ alkyl,cycloalkyl, C₆-C₁₀ aryl, and heteroaryl; or R₁₂ and R_(12A), togetherwith the nitrogen to which they are attached, form a 5-7 memberheterocyclic ring; R₁₃ is H, C₁-C₆ alkyl, cycloalkyl, C₆-C₁₀ aryl,heteroaryl, —C(═O)R₇, —C(═O)NR₉R₁₀, or —C(═S)NR₉R₁₀; X₁ is —O—, —S—,—N(R₈)—; Y is selected from C₁-C₄ alkylene, C₆-C₁₀ arylene,heteroarylene, C₃-C₈ cycloalkylene, heterocyclylene, —O—, —N(R₈)—,—S(O)_(y), —CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—, or —C≡C—;with the proviso that when Y is —O—, —N(R₈)—, or —S(O)_(y), m and ncannot be 0; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; p is from 1 to 4; qis 0, 1, 2; t is 2, 3, or 4; y is 0, 1 or 2; provided that when rings Aand B are phenyl, X is —CH₂CH₂—, q is 0, m and n are 0, and Y is C₁-C₄alkylene, then R₃ and R₄ are the same or different and are each selectedfrom H, —OH, —CH(R₆)—CONR_(8A)R_(8B), provided that R₃ and R₄ are notboth OH, or R₃ and R₄, together with the nitrogen to which they areattached, form a 3-7 member heterocyclic ring; and the stereoisomericforms, mixtures of stereoisomeric forms, or pharmaceutically acceptablesalt and ester forms thereof.
 2. The compound of claim 1, wherein q=1.3. The compound of claim 1, wherein rings A and B, together with thecarbon atoms to which they are attached, are each independently selectedfrom phenylene, thienylene, isothiazolylene, pyridylene, oxazolylene,isoxazolylene, thiazolylene, imidazolylene.
 4. The compound of claim 3,wherein ring A is phenylene.
 5. The compound of claim 4, wherein ring Bis phenylene.
 6. The compound of claim 1, wherein X is a bond, —CH₂CH₂—,—O—, —N(CH₃)—, or —CH═CH—.
 7. The compound of claim 1, wherein Y isphenylene.
 8. The compound of claim 1, wherein Y is C₁-C₄ alkylene. 9.The compound of claim 1, wherein rings A and B are phenylene; X is abond; Y is C₁ alkylene; and m and n=0.
 10. The compound of claim 1,wherein the compound is selected in accordance with the following table:No. A B X Y m n NR₃R₄ II-1 Bnezo Benzo bond —CH₂— 1 0 NH₂ II-2 BenzoBenzo bond —CH₂— 1 0 NMe₂ II-3 Benzo Benzo bond —CH₂— 1 1 NH₂ II-4 BenzoBenzo bond —CH₂— 1 0 NHCH(CH₃)—CONH₂ II-5 Benzo Benzo bond —CH₂— 1 0morpholino II-6 Benzo Benzo bond —CH₂— 2 1 NH₂ II-7 Benzo Benzo bond—CH₂— 2 1 NMe₂ II-8 Benzo Benzo bond —CH(CH₃)— 1 0 NH₂ II-9 Benzo Benzobond —CH₂— 0 0 NHCH(CH₃)—CONH₂ II-10 Benzo Benzo bond

1 0 NH₂ II-11 Benzo Benzo bond —C(CH₃)₂— 1 0 NH₂ II-12 Benzo Benzo bond

1 0 NH₂ II-13 Benzo Benzo —CH₂CH₂— —CH₂— 1 0 NH₂ II-14 Benzo Benzo—CH₂CH₂— —CH(CH₃)— 1 0 NH₂ II-15 Benzo Benzo bond

1 0 NH₂ II-16 Benzo Benzo bond

1 0 NH₂ II-17 Benzo Benzo bond

1 0 NMe₂ II-18 Benzo Benzo —CH═CH— —CH₂— 2 1 NH₂ II-19 Benzo Benzo—CH═CH— —C(CH₃)₂— 1 0 NH₂ II-20 Benzo Benzo —O— —CH₂— 2 1 NH₂ II-21Benzo Benzo —O— —CH(CH₃)— 1 0 NH₂ II-22 2,3-Thieno 2,3-Thieno bond —CH₂—0 0 NH₂ II-23 Benzo Benzo bond —CH₂— 0 0 NH₂ II-24 Benzo Benzo bond—CH₂— 0 0 NHCH(CH₃)—CONMe₂ II-25 Benzo Benzo —CH₂CH₂— —CH₂— 0 0 NH₂II-26 Benzo Benzo —CH₂CH₂— —CH₂— 0 0 N(CH₃)₂ II-27 Benzo Benzo —O— —CH₂—0 0 NH₂ II-28 Benzo Benzo —N(CH₃)— —CH₂— 0 0 NH₂ II-29 Benzo Benzo —S——CH₂— 0 0 NH₂ II-30 Benzo Benzo bond —CH₂— 0 0 NH(CH₃) II-31 Benzo Benzobond —CH₂— 0 0 NH(CH₂CH₂—NH[t-Boc]) II-32 Benzo Benzo bond —CH₂— 0 0NH(CH₂-[2-pyridyl]) II-33 Benzo Benzo bond —CH₂— 0 0 NH(CH₂-[3-pyridyl])II-34 Benzo Benzo bond —CH₂— 0 0 NH(CH₂CH₂OH) II-35 Benzo Benzo bond—CH₂— 0 0 N(CH₃)₂ II-36 Benzo Benzo bond —CH₂— 0 0

II-37 Benzo Benzo —CH═CH— —CH₂— 0 0 NH₂ II-38 Benzo Benzo bond

1 0 N(CH₃)₂ II-39 Benzo Benzo bond —CH₂— 0 0 NHOH II-40 Benzo Benzo bond—CH₂— 0 0 NHCH₂CONH₂ II-41 Benzo Benzo bond —CH₂— 0 0 NH(CH₂)₂—CONH₂II-42 Benzo Benzo bond —CH₂— 0 0 NH(CH₂)₂F II-43 Benzo Benzo bond —CH₂—0 0 NEt₂ II-44 Benzo Benzo bond —CH₂— 0 0 NH—(R)—CH(CH₃)CONH₂ II-45Benzo Benzo bond —CH₂— 0 0 NH—(R)—CH(CH₃)—C₆H₅ II-46 Benzo Benzo bond—CH₂— 0 0 NH—(S)—CH(CH₃)—CH₂OH II-47 Benzo Benzo bond —CH₂— 0 0NH—(S)—CH(CH₃)—CO₂Me II-48 Benzo Benzo bond —CH₂— 0 0NH—(S)—CH(CH₃)CONH₂ II-49 Benzo Benzo bond —CH₂— 0 0 NH—(S)—CH(CH₃)CONH₂II-50 Benzo Benzo bond —CH₂— 0 0 NH—(S)—CH(CH₃)CONMe₂ II-51 Benzo Benzobond —CH₂— 0 0 NH—(S)—CH(CH₂OH)CONH₂ II-52 Benzo Benzo bond —CH₂— 0 0NH—(S)—CH[CH(OH)CH₃]CONH₂ II-53 Benzo Benzo bond —CH₂— 0 0

II-54 Benzo Benzo bond —CH(CH₃)— 0 0 NH₂ II-55 Benzo Benzo —O— —CH₂— 1 0NH₂ II-56 Benzo Benzo —O— —CH₂— 0 0 N(CH₃)₂ II-57 Benzo Benzo —O— —CH₂—0 0 NH—(S)—CH(CH₃)CONH₂ II-58 Benzo Benzo —CH₂CH₂— —CH₂CH₂— 0 0 NH₂II-59 Benzo Benzo —CH₂CH₂— —CH(CH₃)— 1 0 NH₂ II-60 Benzo Benzo bond

0 0 NH₂ II-61 Benzo Benzo —CH═CH— —C(CH₃)₂— 1 0 NH₂ II-62 Benzo Benzo—CH₂CH₂— —CH₂— 1 0 NH—CH(CH₃)CONH₂ II-63 Benzo Benzo —CH₂CH₂— —CH₂— 1 0morpholino II-64 Benzo Benzo bond

1 0 NH₂ II-65 Benzo Benzo bond —CH═CH— 0 0 NH₂ II-66

Benzo bond —CH₂— 0 0 NH₂.


11. A method of treating diseases or disorders in a subject in needthereof comprising administering a therapeutically effective amount of acompound of claim 1 to said subject.
 12. The method of claim 11, whereinthe compound is administered for the treatment of sleepiness, tiredness,Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eatingdisorders, attention deficit hyperactivity disorder, cognitivedysfunction or fatigue; and for the promotion of wakefulness,stimulation of appetite, or stimulation of weight gain.
 13. The methodof claim 11, wherein the compound is administered for the treatment ofdisorders associated with hypofunctionality of the cerebral cortex. 14.The method of claim 13, wherein the compound is administered for thetreatment of depression, schizophrenia, and chronic fatigue syndrome.15. A pharmaceutical composition comprising a compound of claim 1 inadmixture with one or more pharmaceutically acceptable excipients. 16.The compound of claim 1, wherein the compound is selected in accordancewith the following table: No. A B X Y m n NR₃R₄ II-1 Bnezo Benzo bond—CH₂— 1 0 NH₂ II-2 Benzo Benzo bond —CH₂— 1 0 NMe₂ II-3 Benzo Benzo bond—CH₂— 1 1 NH₂ II-4 Benzo Benzo bond —CH₂— 1 0 NHCH(CH₃)—CONH₂ II-6 BenzoBenzo bond —CH₂— 2 1 NH₂ II-7 Benzo Benzo bond —CH₂— 2 1 NMe₂ II-8 BenzoBenzo bond —CH(CH₃)— 1 0 NH₂ II-10 Benzo Benzo bond

1 0 NH₂ II-11 Benzo Benzo bond —C(CH₃)₂— 1 0 NH₂ II-12 Benzo Benzo bond

1 0 NH₂ II-13 Benzo Benzo —CH₂CH₂— —CH₂— 1 0 NH₂ II-14 Benzo Benzo—CH₂CH₂— —CH(CH₃)— 1 0 NH₂ II-15 Benzo Benzo bond

1 0 NH₂ II-24 Benzo Benzo bond —CH₂— 0 0 NHCH(CH₃)—CONMe₂ II-27 BenzoBenzo —O— —CH₂— 0 0 NH₂ II-30 Benzo Benzo bond —CH₂— 0 0 NH(CH₃) II-31Benzo Benzo bond —CH₂— 0 0 NH(CH₂CH₂—NH[t-Boc]) II-32 Benzo Benzo bond—CH₂— 0 0 NH(CH₂-[2-pyridyl]) II-33 Benzo Benzo bond —CH₂— 0 0NH(CH₂-[3-pyridyl]) II-34 Benzo Benzo bond —CH₂— 0 0 NH(CH₂CH₂OH) II-35Benzo Benzo bond —CH₂— 0 0 N(CH₃)₂ II-36 Benzo Benzo bond —CH₂— 0 0

II-37 Benzo Benzo —CH═CH— —CH₂— 0 0 NH₂ II-38 Benzo Benzo bond

1 0 N(CH₃)₂ II-39 Benzo Benzo bond —CH₂— 0 0 NHOH II-40 Benzo Benzo bond—CH₂— 0 0 NHCH₂CONH₂ II-41 Benzo Benzo bond —CH₂— 0 0 NH(CH₂)₂—CONH₂II-42 Benzo Benzo bond —CH₂— 0 0 NH(CH₂)₂F II-43 Benzo Benzo bond —CH₂—0 0 NEt₂ II-44 Benzo Benzo bond —CH₂— 0 0 NH—(R)—CH(CH₃)CONH₂ II-45Benzo Benzo bond —CH₂— 0 0 NH—(R)—CH(CH₃)—C₆H₅ II-46 Benzo Benzo bond—CH₂— 0 0 NH—(S)—CH(CH₃)—CH₂OH II-47 Benzo Benzo bond —CH₂— 0 0NH—(S)—CH(CH₃)—CO₂Me II-48 Benzo Benzo bond —CH₂— 0 0NH—(S)—CH(CH₃)CONH₂ II-49 Benzo Benzo bond —CH₂— 0 0 NH—(S)—CH(CH₃)CONH₂II-50 Benzo Benzo bond —CH₂— 0 0 NH—(S)—CH(CH₃)CONMe₂ II-51 Benzo Benzobond —CH₂— 0 0 NH—(S)—CH(CH₂OH)CONH₂ II-52 Benzo Benzo bond —CH₂— 0 0NH—(S)—CH[CH(OH)CH₃]CONH₂ II-53 Benzo Benzo bond —CH₂— 0 0

II-54 Benzo Benzo bond —CH(CH₃)— 0 0 NH₂ II-56 Benzo Benzo —O— —CH₂— 0 0N(CH₃)₂ II-57 Benzo Benzo —O— —CH₂— 0 0 NH—(S)—CH(CH₃)CONH₂ II-58 BenzoBenzo —CH₂CH₂— —CH₂CH₂— 0 0 NH₂ II-59 Benzo Benzo —CH₂CH₂— —CH(CH₃)— 1 0NH₂ II-60 Benzo Benzo bond

0 0 NH₂ II-61 Benzo Benzo —CH═CH— —C(CH₃)₂— 1 0 NH₂ II-62 Benzo Benzo—CH₂CH₂— —CH₂— 1 0 NH—CH(CH₃)CONH₂ II-63 Benzo Benzo —CH₂CH₂— —CH₂— 1 0morpholino II-64 Benzo Benzo bond

1 0 NH₂ II-65 Benzo Benzo bond —CH═CH— 0 0 NH₂ II-66

Benzo bond —CH₂— 0 0 NH₂.


17. The compound of claim 1, wherein when rings A and B are phenyl, X is—CH₂CH₂—, or —CH═CH—, q is 0, and —(CH₂)_(m)—Y—(CH₂)_(n)— is C₁-C₄alkylene, then one of R₃ and R₄ are the same or different and are eachselected from —OH, —CH(R₆)—CONR_(8A)R_(8B).
 18. The compound of claim 1wherein ring A is unsubstituted phenyl, ring B is unsubstituted, X is abond, —CH₂CH₂—, —O—, —S(O)_(n)—, —N(R₈)—, —CH═CH—, or —CH₂—CH═CH—,wherein R₈ is H or C₁-C₄ alkyl; m and n are 0; Y= —C(R₁)(R₂), wherein R₁and R₂ are each independently selected from H or C₁-C₄ alkyl; and R₃ andR₄ are the same or different and are each selected from H, C₁-C₄ alkyl,—OH, —CH(R₆)—CONR_(8A)R_(8B), wherein R_(8A) and R_(8B) are eachindependently H or C₁-C₄ alkyl, provided that R₃ and R₄ are not both OH;or R₃ and R₄, together with the nitrogen to which they are attached,form an unsubstituted 3-7 member heterocyclic ring.
 19. The compound ofclaim 1, wherein Y is —O—, —S(O)_(y)—, or —N(R₈)—.
 20. The compound ofclaim 1, wherein Y is —CR_(8A)═CR_(8B)—, —CH═CH—CH(R₈)—, —CH(R₈)—CH═CH—,or —(C≡C—.
 21. The compound of claim 1, wherein Y is C₆-C₁₀ arylene orheteroarylene.
 22. The compound of claim 1, wherein m=0 or 1 and n=0 or1, and Y is


23. The compound of claim 1, wherein Y is C₃-C₈ cycloalkylene orheterocyclylene.
 24. The compound of claim 23, wherein Y is


25. The compound of claim 1, wherein at least one of rings A and B arethienylene.
 26. The compound of claim 25, wherein ring A is phenyleneand ring B is 2,3-thienylene.
 27. The compound of claim 6, wherein X isa bond.
 28. The compound of claim 1, wherein rings A and B are phenyl, qis 1, m, n are 0, X is a bond, and Y is C₁-C₄ alkylene or phenylene. 29.The compound of claim 1, wherein rings A and B are phenyl, q is 1, m, nare 0, X is —CH₂CH₂—, —O—, —N(R₈)—, or —CH═CH—, and Y is C₁-C₄ alkyleneor phenylene.